Cyclic AMP-specific phosphodiesterase inhibitors

ABSTRACT

Novel pyrrolidine compounds that are potent and selective inhibitors of PDE4, as well as methods of making the same, are disclosed. Use of the compounds in the treatment of inflammatory diseases and other diseases involving elevated levels of cytokines, as well as central nervous system (CNS) disorders, also is disclosed.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This is a continuation-in-part of U.S. patent application Ser.No. 09/471,846, filed Dec. 23, 1999, pending.

FIELD OF INVENTION

[0002] The present invention relates to a series of compounds that arepotent and selective inhibitors of cyclic adenosine 3′,5′-monophosphatespecific phosphodiesterase (cAMP specific PDE). In particular, thepresent invention relates to a series of novel pyrrolidine compoundsthat are useful for inhibiting the function of cAMP specific PDE, inparticular, PDE4, as well as methods of making the same, pharmaceuticalcompositions containing the same, and their use as therapeutic agents,for example, in treating inflammatory diseases and other diseasesinvolving elevated levels of cytokines and proinflammatory mediators.

BACKGROUND OF THE INVENTION

[0003] Chronic inflammation is a multi-factorial disease complicationcharacterized by activation of multiple types of inflammatory cells,particularly cells of lymphoid lineage (including T lymphocytes) andmyeloid lineage (including granulocytes, macrophages, and monocytes).Proinflammatory mediators, including cytokines, such as tumor necrosisfactor (TNF) and interleukin-1 (IL-1), are produced by these activatedcells. Accordingly, an agent that suppresses the activation of thesecells, or their production of proinflammatory cytokines, would be usefulin the therapeutic treatment of inflammatory diseases and other diseasesinvolving elevated levels of cytokines.

[0004] Cyclic adenosine monophosphate (cAMP) is a second messenger thatmediates the biologic responses of cells to a wide range ofextracellular stimuli. When the appropriate agonist binds to specificcell surface receptors, adenylate cyclase is activated to convertadenosine triphosphate (ATP) to cAMP. It is theorized that the agonistinduced actions of cAMP within the cell are mediated predominately bythe action of cAMP-dependent protein kinases. The intracellular actionsof cAMP are terminated by either a transport of the nucleotide to theoutside of the cell, or by enzymatic cleavage by cyclic nucleotidephosphodiesterases (PDEs), which hydrolyze the 3′-phosphodiester bond toform 5′-adenosine monophosphate (5′-AMP). 5′-AMP is an inactivemetabolite. The structures of cAMP and 5′-AMP are illustrated below.

[0005] Elevated levels of cAMP in human myeloid and lymphoid lineagecells are associated with the suppression of cell activation. Theintracellular enzyme family of PDEs, therefore, regulates the level ofcAMP in cells. PDE4 is a predominant PDE isotype in these cells, and isa major contributor to cAMP degradation. Accordingly, the inhibition ofPDE function would prevent the conversion of cAMP to the inactivemetabolite 5′-AMP and, consequently, maintain higher cAMP levels, and,accordingly, suppress cell activation (see Beavo et al., “CyclicNucleotide Phosphodiesterases: Structure, Regulation and Drug Action,”Wiley and Sons, Chichester, pp. 3-14, (1990)); Torphy et al., Drug Newsand Perspectives, 6, pp. 203-214 (1993); Giembycz et al., Clin. Exp.Allergy, 22, pp. 337-344 (1992)).

[0006] In particular, PDE4 inhibitors, such as rolipram, have been shownto inhibit production of TNFα and partially inhibit IL-1β release bymonocytes (see Semmler et al., Int. J. Immunopharmacol., 15, pp.409-413, (1993); Molnar-Kimber et al., Mediators of Inflammation, 1, pp.411-417, (1992)). PDE4 inhibitors also have been shown to inhibit theproduction of superoxide radicals from human polymorphonuclearleukocytes (see Verghese et al., J. Mol. Cell. Cardiol., 21 (Suppl. 2),S61 (1989); Nielson et al., J. Allergy Immunol., 86, pp. 801-808,(1990)); to inhibit the release of vasoactive amines and prostanoidsfrom human basophils (see Peachell et al., J. Immunol., 148, pp.2503-2510, (1992)); to inhibit respiratory bursts in eosinophils (seeDent et al., J. Pharmacol., 103, pp. 1339-1346, (1991)); and to inhibitthe activation of human T-lymphocytes (see Robicsek et al., Biochem.Pharmacol., 42, pp. 869-877, (1991)).

[0007] Inflammatory cell activation and excessive or unregulatedcytokine (e.g., TNFα and IL-1β) production are implicated in allergic,autoimmune, and inflammatory diseases and disorders, such as rheumatoidarthritis, osteoarthritis, gouty arthritis, spondylitis, thyroidassociated ophthalmopathy, Behcet's disease, sepsis, septic shock,endotoxic shock, gram negative sepsis, gram positive sepsis, toxic shocksyndrome, asthma, chronic bronchitis, adult respiratory distresssyndrome, chronic pulmonary inflammatory disease, such as chronicobstructive pulmonary disease, silicosis, pulmonary sarcoidosis,reperfusion injury of the myocardium, brain, and extremities, fibrosis,cystic fibrosis, keloid formation, scar formation, atherosclerosis,transplant rejection disorders, such as graft vs. host reaction andallograft rejection, chronic glomerulonephritis, lupus, inflammatorybowel disease, such as Crohn's disease and ulcerative colitis,proliferative lymphocyte diseases, such as leukemia, and inflammatorydermatoses, such as atopic dermatitis, psoriasis, and urticaria.

[0008] Other conditions characterized by elevated cytokine levelsinclude brain injury due to moderate trauma (see Dhillon et al., J.Neurotrauma, 12, pp. 1035-1043 (1995); Suttorp et al., J. Clin. Invest.,91, pp. 1421-1428 (1993)), cardiomyopathies, such as congestive heartfailure (see Bristow et al., Circulation, 97, pp. 1340-1341 (1998)),cachexia, cachexia secondary to infection or malignancy, cachexiasecondary to acquired immune deficiency syndrome (AIDS), ARC (AIDSrelated complex), fever myalgias due to infection, cerebral malaria,osteoporosis and bone resorption diseases, keloid formation, scar tissueformation, and pyrexia.

[0009] In particular, TNFα has been identified as having a role withrespect to human acquired immune deficiency syndrome (AIDS). AIDSresults from the infection of T-lymphocytes with Human ImmunodeficiencyVirus (HIV). Although HIV also infects and is maintained in myeloidlineage cells, TNF has been shown to upregulate HIV infection inT-lymphocytic and monocytic cells (see Poli et al., Proc. Natl. Acad.Sci. USA, 87, pp. 782-785, (1990)).

[0010] Several properties of TNFα, such as stimulation of collagenases,stimulation of angiogenesis in vivo, stimulation of bone resorption, andan ability to increase the adherence of tumor cells to endothelium, areconsistent with a role for TNF in the development and metastatic spreadof cancer in the host. TNFα recently has been directly implicated in thepromotion of growth and metastasis of tumor cells (see Orosz et al., J.Exp. Med., 177, pp. 1391-1398, (1993)).

[0011] PDE4 has a wide tissue distribution. There are at least fourgenes for PDE4 of which multiple transcripts from any given gene canyield several different proteins that share identical catalytic sites.The amino acid identity between the four possible catalytic sites isgreater than 85%. Their shared sensitivity to inhibitors and theirkinetic similarity reflect the functional aspect of this level of aminoacid identity. It is theorized that the role of these alternativelyexpressed PDE4 proteins allows a mechanism by which a cell candifferentially localize these enzymes intracellularly and/or regulatethe catalytic efficiency via post translational modification. Any givencell type that expresses the PDE4 enzyme typically expresses more thanone of the four possible genes encoding these proteins.

[0012] Investigators have shown considerable interest in the use of PDE4inhibitors as anti-inflammatory agents. Early evidence indicates thatPDE4 inhibition has beneficial effects on a variety of inflammatorycells such as monocytes, macrophages, T-cells of the Th-1 lineage, andgranulocytes. The synthesis and/or release of many proinflammatorymediators, such as cytokines, lipid mediators, superoxide, and biogenicamines, such as histamine, have been attenuated in these cells by theaction of PDE4 inhibitors. The PDE4 inhibitors also affect othercellular functions including T-cell proliferation, granulocytetransmigration in response to chemotoxic substances, and integrity ofendothelial cell junctions within the vasculature.

[0013] The design, synthesis, and screening of various PDE4 inhibitorshave been reported. Methyl-xanthines, such as caffeine and theophylline,were the first PDE inhibitors discovered, but these compounds arenonselective with respect to which PDE is inhibited. The drug rolipram,an antidepressant agent, was one of the first reported specific PDE4inhibitors. Rolipram, having the following structural formula, has areported 50% Inhibitory Concentration (IC₅₀) of about 200 nM (nanomolar)with respect to inhibiting recombinant human PDE4.

[0014] Investigators have continued to search for PDE4 inhibitors thatare more selective with respect to inhibiting PDE4, that have a lowerIC₅₀ than rolipram, and that avoid the undesirable central nervoussystem (CNS) side effects, such as retching, vomiting, and sedation,associated with the administration of rolipram. One class of compoundsis disclosed in Feldman et al. U.S. Pat. No. 5,665,754. The compoundsdisclosed therein are substituted pyrrolidines having a structuresimilar to rolipram. One particular compound, having structural formula(I), has an IC₅₀ with respect to human recombinant PDE4 of about 2 nM.Inasmuch as a favorable separation of emetic side effect from efficacywas observed, these compounds did not exhibit a reduction in undesirableCNS effects.

[0015] In addition, several companies are now undertaking clinicaltrials of other PDE4 inhibitors. However, problems relating to efficacyand adverse side effects, such as emesis and central nervous systemdisturbances, remain unsolved.

[0016] Accordingly, compounds that selectively inhibit PDE4, and thatreduce or eliminate the adverse CNS side effects associated with priorPDE4 inhibitors, would be useful in the treatment of allergic andinflammatory diseases, and other diseases associated with excessive orunregulated production of cytokines, such as TNF. In addition, selectivePDE4 inhibitors would be useful in the treatment of diseases that areassociated with elevated cAMP levels or PDE4 function in a particulartarget tissue.

SUMMARY OF THE INVENTION

[0017] The present invention is directed to potent and selective PDE4inhibitors useful in treatment of diseases and conditions whereinhibition of PDE4 activity is considered beneficial. The present PDE4inhibitors unexpectedly reduce or eliminate the adverse CNS side effectsassociated with prior PDE4 inhibitors.

[0018] In particular, the present invention is directed to pyrrolidinecompounds having the structural formula (II):

[0019] wherein R¹ is selected from the group consisting of hydrogen,lower alkyl, bridged alkyl (e.g., norbornyl), aryl, cycloalkyl (e.g.,indanyl), a 4-, 5-, or 6-membered saturated heterocycle (e.g.,3-tetrahydrofuryl), heteroaryl, C₁₋₄alkylenearyl, C₁₋₄alkyleneOaryl,C₁₋₄alkyleneheteroaryl, C₁₋₄alkyleneHet, C₂₋₄alkylenearylOaryl,C₁₋₄alkylene bridged alkyl, C₁₋₄alkylenecycloalkyl (e.g.,cyclopentylmethyl), substituted or unsubstituted propargyl (e.g.,—CH₂C≡C—C₆H₅), substituted or unsubstituted allyl (e.g.,—CH₂CH═CH—C₆H₅), and halocycloalkyl (e.g., fluorocyclopentyl);

[0020] R² is selected from the group consisting of hydrogen, methyl, andhalo-substituted methyl, e.g., CHF₂;

[0021] R³ is selected from the group consisting of C(═O)OR⁷, C(═O)R⁷,NHC(═O)OR⁷, C₁₋₃alkyleneC(═O)OR⁸, C₁₋₃alkyleneC(═O)R⁸, C(═NH)NR⁸R⁹,C(═O)NR⁸R⁹, C(═O)C(═O)NR⁸R⁹, C(═O)C(═O)OR⁸, C₁₋₄-alkyleneOR⁸, aryl, C₁₃alkylenearyl, C₁₋₃alkyleneheteroaryl, SO₂heteroaryl, Het, andheteroaryl;

[0022] R⁴ is selected from the group consisting of hydrogen, loweralkyl, haloalkyl, cycloalkyl, and aryl;

[0023] R⁵ is selected from the group consisting of hydrogen, loweralkyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, and aryl;

[0024] R⁶ is selected from the group consisting of hydrogen, loweralkyl, and C(═O)R⁷;

[0025] R⁷ is selected from the group consisting of lower alkyl, branchedor unbranched, C₁₋₄alkylenearyl, cycloalkyl, Het,C₁₋₄alkylenecycloalkyl, heteroaryl, and aryl, each optionallysubstituted with one or more of OC(═O)R⁸, C(═O)OR⁸, OR⁸, NR⁸R⁹, or SR⁸;

[0026] R⁸ and R⁹, same or different, are selected from the groupconsisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl,C(═O)Oalkyl, C(═O)Oaryl, C(═O)alkyl, alkylSO₂, haloalkylSO₂,C(═O)C₁₋₃alkylenearyl, C(═O)OC₁₋₄alkylenearyl, C₁₋₄alkylenearyl, andHet, or R⁸ and R⁹ together form a 4-membered to 7-membered ring;

[0027] R¹⁰ is selected from the group consisting of hydrogen, alkyl,haloalkyl, cycloalkyl, aryl, C(═O)alkyl, C(═O)cycloalkyl, C(═O)aryl,C(═O)Oalkyl, C(═O)Ocycloalkyl, C(═O)aryl, CH₂OH, CH₂Oalkyl, CHO, CN,NO₂, and SO₂R¹¹;

[0028] R¹¹ is selected from the group consisting of alkyl, cycloalkyl,trifluoromethyl, aryl, aralkyl, and NR⁸R⁹; and

[0029] salts and solvates (e.g., hydrates) thereof.

[0030] In another embodiment, the present invention is directed topyrrolidine compounds having a structural formula (IIa):

[0031] wherein R¹ is selected from the group consisting of hydrogen,lower alkyl, bridged alkyl, aryl, cycloalkyl, a 4-, 5-, or 6-memberedsaturated heterocycle, heteroaryl, C₁₋₄alkylenearyl, C₁₋₄alkyleneOaryl,C₁₋₄alkyleneheteroaryl, C₁₋₄alkyleneHet, C₂₋₄alkylenearylOaryl,C₁₋₄alkylene bridged alkyl, C₁₋₄alkylenecycloalkyl, substituted orunsubstituted propargyl, substituted or unsubstituted allyl, andhalocycloalkyl;

[0032] R² is selected from the group consisting of hydrogen, methyl, andhalo-substituted methyl;

[0033] R³ is selected from the group consisting of hydrogen,C₁₋₄alkylenearyl, and C(═O)C₁₋₃alkyleneO-C₁₋₃alkylenearyl;

[0034] R⁴ is selected from the group consisting of hydrogen, loweralkyl, haloalkyl, cycloalkyl, and aryl;

[0035] R⁵ is selected from the group consisting of hydrogen, loweralkyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, and aryl;

[0036] R⁶ is selected from the group consisting of hydrogen, loweralkyl, and C(═O)R⁷;

[0037] R⁷ is selected from the group consisting of lower alkyl, branchedor unbranched, C₁₋₄alkylenearyl, cycloalkyl, Het,C₁₋₄alkylenecycloalkyl, heteroaryl, and aryl, each optionallysubstituted with one or more of OC(═O)R⁸, C(═O)OR⁸, OR⁸, NR⁸R⁹, and SR⁸;and

[0038] R⁸ and R⁹, same or different, are selected from the groupconsisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl,C(═O)Oalkyl, C(═O)alkyl, C(═O)Oaryl, alkylSO₂, haloalkylSO₂,C(═O)C₁₋₃alkylenearyl, C(═O)OC₁₋₄alkylenearyl, C₁₋₄alkylenearyl, andHet, or R⁸ and R⁹ together form a 4-membered to 7-membered ring;

[0039] R¹⁰ is selected from the group consisting of hydrogen, alkyl,haloalkyl, cycloalkyl, aryl, C(═O)alkyl, C(═O)cycloalkyl, C(═O)aryl,C(═O)Oalkyl, C(═O)Ocycloalkyl, C(═O)aryl, CH₂OH, CH₂Oalkyl, CHO, CN,NO₂, and SO₂R¹¹; and

[0040] R¹¹ is selected from the group consisting of alkyl, cycloalkyl,trifluoromethyl, aryl, aralkyl, and NR⁸R⁹; and

[0041] salts and solvates (e.g., hydrates) thereof.

[0042] The present invention also is directed to pharmaceuticalcompositions containing one or more of the compounds of structuralformula (II), to use of the compounds and compositions containing thecompounds in the treatment of a disease or disorder, and to methods ofpreparing compounds and intermediates involved in the synthesis of thecompounds of structural formula (II).

[0043] The present invention also is directed to methods of (a) treatinga mammal having a condition where inhibition of PDE4 provides a benefit,(b) modulating cAMP levels in a mammal, (c) reducing TNFα levels in amammal, (d) suppressing inflammatory cell activation in a mammal, and(e) inhibiting PDE4 function in a mammal by administering to the mammala therapeutically effective amount of a compound of structural formula(II) or a composition containing a composition of structural formula(II).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] The present invention is directed to compounds having thestructural formula (II):

[0045] wherein R¹ is selected from the group consisting of hydrogen,lower alkyl, bridged alkyl (e.g., norbornyl), aryl, cycloalkyl (e.g.,indanyl), a4-, 5-, or 6-membered saturated heterocycle (e.g.,3-tetrahydrofuryl), heteroaryl, C₁₋₄alkylenearyl, C₁₋₄alkyleneOaryl,C₁₋₄alkyleneheteroaryl, C₁₋₄alkyleneHet, C₂₋₄alkylenearylOaryl,C₁₋₄alkylene bridged alkyl, C₁₋₄alkylenecycloalkyl (e.g.,cyclopentylmethyl), substituted or unsubstituted propargyl (e.g.,—CH₂C≡C—C₆H₅), substituted or unsubstituted allyl (e.g.,—CH₂CH═CH—C₆H₅), and halocycloalkyl (e.g., fluorocyclopentyl);

[0046] R² is selected from the group consisting of hydrogen, methyl, andhalo-substituted methyl, e.g., CHF₂;

[0047] R³ is selected from the group consisting of C(═O)OR⁷, —C(═O)R⁷,NHC(═O)OR⁷, C₁₋₃alkyleneC(═O)OR⁸, C₁₋₃alkyleneC(═O)R⁸, C(═NH)NR⁸R⁹,C(═O)NR⁸R⁹, C(═O)C(═O)NR⁸R⁹, C(═O)C(═O)OR⁸, C₁₋₄alkyleneOR⁸, aryl,C₁₋₃alkylenearyl, C₁₋₃alkyleneheteroaryl, SO₂heteroaryl, Het, andheteroaryl;

[0048] R⁴ is selected from the group consisting of hydrogen, loweralkyl, haloalkyl, cycloalkyl, and aryl;

[0049] R⁵ is selected from the group consisting of hydrogen, loweralkyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, and aryl;

[0050] R⁶ is selected from the group consisting of hydrogen, loweralkyl, and C(═O)R⁷;

[0051] R⁷ is selected from the group consisting of lower alkyl, branchedor unbranched, C₁₋₄alkylenearyl, cycloalkyl, Het,C₁₋₄alkylenecycloalkyl, heteroaryl, and aryl, each optionallysubstituted with one or more of OC(═O)R⁸, C(═O)OR⁸, OR⁸, NR⁸R⁹, or SR⁸;

[0052] R⁸ and R⁹, same or different, are selected from the groupconsisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl,C(═O)Oalkyl, C(═O)Oaryl, C(═O)alkyl, alkylSO₂, haloalkylSO₂,C(═O)C₁₋₃alkylenearyl, C(═O)OC₁₋₄alkylenearyl, C₁₋₄alkylenearyl, andHet, or R⁸ and R⁹ together form a 4-membered to 7-membered ring;

[0053] R¹⁰ is selected from the group consisting of hydrogen, alkyl,haloalkyl, cycloalkyl, aryl, C(═O)alkyl, C(═O)cycloalkyl, C(═O)aryl,C(═O)Oalkyl, C(═O)Ocycloalkyl, C(═O)aryl, CH₂OH, CH₂Oalkyl, CHO, CN,NO₂, and SO₂R¹¹;

[0054] R¹¹ is selected from the group consisting of alkyl, cycloalkyl,trifluoromethyl, aryl, aralkyl, and NR⁸R⁹; and

[0055] salts and solvates (e.g., hydrates) thereof.

[0056] In another embodiment, the present invention is directed topyrrolidine compounds having a structural formula (IIa):

[0057] wherein R¹ is selected from the group consisting of hydrogen,lower alkyl, bridged alkyl, aryl, cycloalkyl, a 4-, 5-, or 6-memberedsaturated heterocycle, heteroaryl, C₁₋₄alkylenearyl, C₁₋₄alkyleneOaryl,C₁₋₄alkyleneheteroaryl, C₁₋₄alkyleneHet, C₂₋₄alkylenearylOaryl,C₁₋₄alkylene bridged alkyl, C₁₋₄alkylenecycloalkyl, substituted orunsubstituted propargyl, substituted or unsubstituted allyl, andhalocycloalkyl;

[0058] R² is selected from the group consisting of hydrogen, methyl, andhalo-substituted methyl;

[0059] R³ is selected from the group consisting of hydrogen,C₁₋₄alkylenearyl, and C(═O)C₁₋₃alkyleneOC₁₋₃alkylenearyl;

[0060] R⁴ is selected from the group consisting of hydrogen, loweralkyl, haloalkyl, cycloalkyl, and aryl;

[0061] R⁵ is selected from the group consisting of hydrogen, loweralkyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, and aryl;

[0062] R⁶ is selected from the group consisting of hydrogen, loweralkyl, and C(═O)R⁷;

[0063] R⁷ is selected from the group consisting of lower alkyl, branchedor unbranched, C₁₋₄alkylenearyl, cycloalkyl, Het,C₁₋₄alkylenecycloalkyl, heteroaryl, and aryl, each optionallysubstituted with one or more of OC(═O)R⁸, C(═O)OR⁸, OR⁸, NR⁸R⁹, and SR⁸;and

[0064] R⁸ and R⁹, same or different, are selected from the groupconsisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl,C(═O)Oalkyl, C(═O)alkyl, C(═O)Oaryl, alkylSO₂, haloalkylSO₂,C(═O)C₁₋₃alkylenearyl, C(═O)OC₁₋₄alkylenearyl, C₁₋₄alkylenearyl, andHet, or R⁸ and R⁹ together form a 4-membered to 7-membered ring;

[0065] R¹⁰ is selected from the group consisting of hydrogen, alkyl,haloalkyl, cycloalkyl, aryl, C(═O)alkyl, C(═O)cycloalkyl, C(═O)aryl,C(═O)Oalkyl, C(═O)Ocycloalkyl, C(═O)aryl, CH₂OH, CH₂Oalkyl, CHO, CN,NO₂, and SO₂R¹¹; and

[0066] R¹¹ is selected from the group consisting of alkyl, cycloalkyl,trifluoromethyl, aryl, aralkyl, and NR⁸R⁹; and

[0067] salts and solvates (e.g., hydrates) thereof.

[0068] As used herein, the term “alkyl,” alone or in combination, isdefined to include straight chain and branched chain saturatedhydrocarbon groups containing one to 16 carbon atoms, either substitutedor unsubstituted. The term “lower alkyl” is defined herein as an alkylgroup having one through six carbon atoms (C₁-C₆). Examples of loweralkyl groups include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, isobutyl, tertiary butyl, isopentyl, n-butyl, neopentyl,n-hexyl, and the like. The term “alkynyl” refers to an unsaturated alkylgroup that contains a carbon-carbon triple bond.

[0069] The term “bridged alkyl” is defined herein as a C₆-C₁₆ bicyclicor polycyclic hydrocarbon group, for example, norboryl, adamantyl,bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl,bicyclo[4.1.0]heptyl, bicyclo[3.1.0]hexyl, and decahydronaphthyl,substituted or unsubstituted.

[0070] The term “cycloalkyl” is defined herein to include monocyclic orfused polycyclic C₃-C₁₀ aliphatic hydrocarbon groups. Examples ofcycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclohexyl, decahydronaphthlene, and cyclopentyl. As usedherein, “cycloalkyl” also encompasses cyclic C₃-C₇ aliphatic hydrocarbongroups fused to an aryl ring. For example, indanyl andtetrahydronaphthalenyl are cycloalkyl groups as defined herein.

[0071] An alkyl, bridged alkyl, or cycloalkyl group optionally can besubstituted with one or more, typically one to three, substituents, forexample, lower alkyl, cycloalkyl, haloalkyl, e.g., CF₃—, halo, hydroxy,alkoxy, aryl, heteroaryl, and Het.

[0072] The term “alkylene” refers to an alkyl group having asubstituent. For example, the term “C₁₋₃alkylenecycloalkyl” refers to analkyl group containing one to three carbon atoms, and substituted with acycloalkyl group. An example of “C₁₋₃alkylenearyl” is benzyl.

[0073] The term “haloalkyl” is defined herein as an alkyl groupsubstituted with one or more halo substituents, either fluro, chloro,bromo, iodo, or combinations thereof. Similarly, “halocycloalkyl” and“haloaryl” are defined as a cycloalkyl or an aryl group having one ormore halo substituents.

[0074] The term “aryl,” alone or in combination, is defined herein as amonocyclic or polycyclic aromatic group, preferably a monocyclic orbicyclic aromatic group, e.g., phenyl or naphthyl, that can beunsubstituted or substituted, for example, with one or more, and inparticular one to three, substituents selected from halo, alkyl, phenyl,substituted phenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl,haloalkyl, nitro, amino, alkylamino, acylamino, alkylthio,alkylsulfinyl, and alkylsulfonyl. Exemplary aryl groups include phenyl,naphthyl, biphenyl, tetrahydronaphthyl, indanyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-methylphenyl,4-methoxyphenyl, 4-trifluoromethylphenyl, 4-nitrophenyl, and the like.

[0075] The term “heteroaryl” is defined herein as a monocyclic orbicyclic ring system containing one or two aromatic rings and containingat least one nitrogen, oxygen, or sulfur atom in an aromatic ring, andwhich can be unsubstituted or substituted, for example, with one ormore, and in particular one to three, substituents, like halo, alkyl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, aryl, haloaryl,nitro, amino, alkylamino, acylamino, alkylthio, alkylsulfinyl, andalkylsulfonyl. Examples of heteroaryl groups include thienyl, furyl,pyridyl, oxazolyl, 1,2,4-oxadiazol-3-yl, quinolyl, isoquinolyl, indolyl,triazolyl, isothiazolyl, isoxazolyl, imidizolyl, benzothiazolyl,pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.

[0076] The terms “heterocycle” and “Het” are defined as a 4-, 5-, or6-membered nonaromatic ring having one or more, typically one to three,heteroatoms selected from oxygen, nitrogen, and sulfur present in thering, and optionally substituted with alkyl, halo, aryl, alkoxy,C₁₋₃alkyleneHet, C₁₋₃alkyleneamino, C₁₋₃alkylenealkylamino, andhaloaryl. Nonlimiting examples include tetrahydrofuran, tetrahydropyran,piperidine, piperazine, sulfolane, morpholine, 1,3-dioxolane,tetrahydropyran, dioxane, trimethyleneoxide, and the like.

[0077] The term “halogen” or “halo” is defined herein to includefluorine, chlorine, bromine, and iodine.

[0078] The term “alkoxy” and “aryloxy” are defined as —OR, wherein R isalkyl or aryl, respectively.

[0079] The term “alkoxyalkyl” is defined as an alkoxy group appended toan alkyl group.

[0080] The term “propargyl” is defined as R—C≡C—CH₂—, wherein R ishydrogen, lower alkyl, haloalkyl, cycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0081] The term “allyl” is defined as R—CH═CHCH₂—, wherein R ishydrogen, lower alkyl, haloalkyl, cycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0082] The term “hydroxy” is defined as —OH.

[0083] The term “hydroxyalkyl” is defined as a hydroxy group appended toan alkyl group.

[0084] The term “amino” is defined as —NH₂.

[0085] The term “alkylamino” is defined as —NR₂ wherein at least one Ris alkyl and the second R is alkyl or hydrogen.

[0086] The term “acylamino” is defined as RC(═O)NH, wherein R is alkylor aryl.

[0087] The term “nitro” is defined as —NO₂.

[0088] The term “alkylthio” is defined as —SR, where R is alkyl.

[0089] The term “alkylsulfinyl” is defined as R—S(O)₂, where R is alkyl.

[0090] The term “alkylsulfonyl” is defined as R—S (O₃), where R isalkyl.

[0091] In preferred embodiments, R⁵ is methyl, R⁷ is methyl or benzyl,R² is methyl or difluoromethyl, R⁴ is selected from the group consistingof hydrogen, methyl, trifluoromethyl, cyclopropyl, benzyl, and phenyl,and R⁶ is selected from the group consisting of hydrogen, acetyl, andbenzoyl. Preferably, R¹ is selected from the group consisting of

[0092] Preferably, R³ is selected from the group consisting of

[0093] wherein Ac is CH₃C(═O) and tBu is C(CH₃)₃.

[0094] In most preferred embodiments, R¹ is selected from the groupconsisting of cyclopentyl, benzyl, tetrahydrofuryl, indanyl, norbornyl,phenethyl, phenylbutyl, methylenecyclopropyl, methylenetetrahydrofuryl,ethylenethienyl, C₁₋₄alkylenecyclopentyl, methyleneindanyl,C₁₋₄alkylenephenyl, phenylpropargyl, phenylallyl,3-(4-chlorophenyl)-(1,2,4-oxadiazol-5-yl)methyl, C₁₋₄ alkylenephenoxy,C₁₋₄alkylenebiphenyl, C₁₋₄alkylenecyclohexyl, pyranyl, methylene bridgedalkyl, tetrahydronaphtyl, decahydronaphthyl, and C₁₋₆alkyl, wherein R¹is optionally substituted with one or more phenyl, hydroxy, methoxy,methyl, ethyl, trifluoromethyl, fluoro, phenoxy, t-butyl, methoxy,cyclopropyl, and halophenyl; R² is selected from the group consisting ofmethyl and difluoromethyl; R³ is selected from the group consisting ofCO₂CH₃, C(═O)CH₂OH, C(═O)CH(CH₃)OH, C(═O)C(CH₃)₂OH, C(═O)C(═O)NH₂,C(═O)C(═O)OH, C(═O)CH₂NH₂, C(═O)CH(OH)CH₂OH, C (═O)CH(OH)CH₂CH₂CH₃,

[0095] R⁴ is hydrogen; R⁵ is methyl; R⁶ is hydrogen; and R⁸ and R⁹,independently, are selected from the group consisting of hydrogen andlower alkyl, or form a 5-membered or 6-membered ring.

[0096] The present invention includes all possible stereoisomers andgeometric isomers of compounds of structural formula (II), and includesnot only racemic compounds but also the optically active isomers aswell. When a compound of structural formula (II) is desired as a singleenantiomer, it can be obtained either by resolution of the final productor by stereospecific synthesis from either isomerically pure startingmaterial or use of a chiral auxiliary reagent, for example, see Z. Ma etal., Tetrahedron: Asymmetry, 8(6), pages 883-888 (1997). Resolution ofthe final product, an intermediate, or a starting material can beachieved by any suitable method known in the art. Additionally, insituations where tautomers of the compounds of structural formula (II)are possible, the present invention is intended to include alltautomeric forms of the compounds. As demonstrated hereafter, specificstereoisomers exhibit an exceptional ability to inhibit PDE4 withoutmanifesting the adverse CNS side effects typically associated with PDE4inhibitors.

[0097] In particular, it is generally accepted that biological systemscan exhibit very sensitive activities with respect to the absolutestereochemical nature of compounds. (See, E. J. Ariens, MedicinalResearch Reviews, 6:451-466 (1986); E. J. Ariens, Medicinal ResearchReviews, 7:367-387 (1987); K. W. Fowler, Handbook of Stereoisomers:Therapeutic Drugs, CRC Press, edited by Donald P. Smith, pp. 35-63(1989); and S. C. Stinson, Chemical and Engineering News, 75:38-70(1997).) For example, rolipram is a stereospecific PDE4 inhibitor thatcontains one chiral center. The (−)-enantiomer of rolipram has a higherpharmacological potency than the (+)-enantiomer, which could be relatedto its potential antidepressant action. Schultz et al.,Naunyn-Schmiedeberg's Arch Pharmacol, 333:23-30 (1986). Furthermore, themetabolism of rolipram appears stereospecific with the (+)-enantiomerexhibiting a faster clearance rate than the (−)-enantiomer. Krause etal., Xenobiotica, 18:561-571 (1988). Finally, a recent observationindicated that the (−)-enantiomer of rolipram (R-rolipram) is aboutten-fold more emetic than the (+)-enantiomer (S-rolipram). A. Robichaudet al.; Neuropharmacology, 38:289-297 (1999). This observation is noteasily reconciled with differences in test animal disposition torolipram isomers and the ability of rolipram to inhibit the PDE4 enzyme.The compounds of the present invention can have three or more chiralcenters. As shown below, compounds of a specific stereochemicalorientation exhibit similar PDE4 inhibitory activity and pharmacologicalactivity, but altered CNS toxicity and emetic potential.

[0098] Accordingly, preferred compounds of the present invention havethe structural formula (III):

[0099] The compounds of structural formula (III) are potent andselective PDE4 inhibitors, and do not manifest the adverse CNS effectsand emetic potential demonstrated by stereoisomers of a compound ofstructural formula (III).

[0100] Compounds of structural formula (II) which contain acidicmoieties can form pharmaceutically acceptable salts with suitablecations. Suitable pharmaceutically acceptable cations include alkalimetal (e.g., sodium or potassium) and alkaline earth metal (e.g.,calcium or magnesium) cations. The pharmaceutically acceptable salts ofthe compounds of structural formula (II), which contain a basic center,are acid addition salts formed with pharmaceutically acceptable acids.Examples include the hydrochloride, hydrobromide, sulfate or bisulfate,phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate,maleate, lactate, citrate, tartrate, gluconate, methanesulfonate,benzenesulphonate, and p-toluenesulphonate salts. In light of theforegoing, any reference to compounds of the present invention appearingherein is intended to include compounds of structural formula (II), aswell as pharmaceutically acceptable salts and solvates thereof.

[0101] The compounds of the present invention can be therapeuticallyadministered as the neat chemical, but it is preferable to administercompounds of structural formula (II) as a pharmaceutical composition orformulation. Accordingly, the present invention further provides forpharmaceutical formulations comprising a compound of structural formula(II), together with one or more pharmaceutically acceptable carriersand, optionally, other therapeutic and/or prophylactic ingredients. Thecarriers are “acceptable” in the sense of being compatible with theother ingredients of the formulation and not deleterious to therecipient thereof.

[0102] In particular, a selective PDE4 inhibitor of the presentinvention is useful alone or in combination with a secondantiinflammatory therapeutic agent, for example, a therapeutic agenttargeting TNFα, such as ENBREL® or REMICADE®, which have utility intreating rheumatoid arthritis. Likewise, therapeutic utility of IL-1antagonism has also been shown in animal models for rheumatoidarthritis. Thus, it is envisioned that IL-1 antagonism, in combinationwith PDE4 inhibition, which attenuates TNFα, would be efficacious.

[0103] The present PDE4 inhibitors are useful in the treatment of avariety of allergic, autoimmune, and inflammatory diseases.

[0104] The term “treatment” includes preventing, lowering, stopping, orreversing the progression of severity of the condition or symptoms beingtreated. As such, the term “treatment” includes both medical therapeuticand/or prophylactic administration, as appropriate.

[0105] In particular, inflammation is a localized, protective responseelicited by injury or destruction of tissues, which serves to destroy,dilute or wall off (i.e., sequester) both the injurious agent and theinjured tissue. The term “inflammatory disease,” as used herein, meansany disease in which an excessive or unregulated inflammatory responseleads to excessive inflammatory symptoms, host tissue damage, or loss oftissue function. Additionally, the term “autoimmune disease,” as usedherein, means any group of disorders in which tissue injury isassociated with humoral or cell-mediated responses to the body's ownconstituents. The term “allergic disease,” as used herein, means anysymptoms, tissue damage, or loss of tissue function resulting fromallergy. The term “arthritic disease,” as used herein, means any of alarge family of diseases that are characterized by inflammatory lesionsof the joints attributable to a variety of etiologies. The term“dermatitis,” as used herein, means any of a large family of diseases ofthe skin that are characterized by inflammation of the skin attributableto a variety of etiologies. The term “transplant rejection,” as usedherein, means any immune reaction directed against grafted tissue(including organ and cell (e.g., bone marrow)), characterized by a lossof function of the grafted and surrounding tissues, pain, swelling,leukocytosis and thrombocytopenia.

[0106] The present invention also provides a method of modulating cAMPlevels in a mammal, as well as a method of treating diseasescharacterized by elevated cytokine levels.

[0107] The term “cytokine,” as used herein, means any secretedpolypeptide that affects the functions of other cells, and thatmodulates interactions between cells in the immune or inflammatoryresponse. Cytokines include, but are not limited to monokines,lymphokines, and chemokines regardless of which cells produce them. Forinstance, a monokine is generally referred to as being produced andsecreted by a monocyte, however, many other cells produce monokines,such as natural killer cells, fibroblasts, basophils, neutrophils,endothelial cells, brain astrocytes, bone marrow stromal cells,epidermal keratinocytes, and B-lymphocytes. Lymphokines are generallyreferred to as being produced by lymphocyte cells. Examples of cytokinesinclude, but are not limited to, interleukin-1 (IL-1), interleukin-6(IL-6), Tumor Necrosis Factor alpha (TNFα), and Tumor Necrosis Factorbeta (TNFβ).

[0108] The present invention further provides a method of reducing TNFlevels in a mammal, which comprises administering an effective amount ofa compound of structural formula (II) to the mammal. The term “reducingTNF levels,”as used herein, means either:

[0109] a) decreasing excessive in vivo TNF levels in a mammal to normallevels or below normal levels by inhibition of the in vivo release ofTNF by all cells, including but not limited to monocytes or macrophages;or

[0110] b) inducing a down-regulation, at the translational ortranscription level, of excessive in vivo TNF levels in a mammal tonormal levels or below normal levels; or

[0111] c) inducing a down-regulation, by inhibition of the directsynthesis of TNF as a postranslational event.

[0112] Moreover, the compounds of the present invention are useful insuppressing inflammatory cell activation. The term “inflammatory cellactivation,” as used herein, means the induction by a stimulus(including, but not limited to, cytokines, antigens or auto-antibodies)of a proliferative cellular response, the production of solublemediators (including but not limited to cytokines, oxygen radicals,enzymes, prostanoids, or vasoactive amines), or cell surface expressionof new or increased numbers of mediators (including, but not limited to,major histocompatability antigens or cell adhesion molecules) ininflammatory cells (including but not limited to monocytes, macrophages,T lymphocytes, B lymphocytes, granulocytes, polymorphonuclearleukocytes, mast cells, basophils, eosinophils, dendritic cells, andendothelial cells). It will be appreciated by persons skilled in the artthat the activation of one or a combination of these phenotypes in thesecells can contribute to the initiation, perpetuation, or exacerbation ofan inflammatory condition.

[0113] The compounds of the present-invention also are useful in causingairway smooth muscle relaxation, bronchodilation, and prevention ofbronchoconstriction.

[0114] The compounds of the present invention, therefore, are useful intreating such diseases as arthritic diseases (such as rheumatoidarthritis), osteoarthritis, gouty arthritis, spondylitis,thyroid-associated ophthalmopathy, Behcet disease, sepsis, septic shock,endotoxic shock, gram negative sepsis, gram positive sepsis, toxic shocksyndrome, asthma, chronic bronchitis, allergic rhinitis, allergicconjunctivitis, vernal conjunctivitis, eosinophilic granuloma, adult(acute) respiratory distress syndrome (ARDS), chronic pulmonaryinflammatory disease (such as chronic obstructive pulmonary disease),silicosis, pulmonary sarcoidosis, reperfusion injury of the myocardium,brain or extremities, brain or spinal cord injury due to minor trauma,fibrosis including cystic fibrosis, keloid formation, scar tissueformation, atherosclerosis, autoimmune diseases, such as systemic lupuserythematosus (SLE) and transplant rejection disorders (e.g., graft vs.host (GvH) reaction and allograft rejection), chronicglomerulonephritis, inflammatory bowel diseases, such as Crohn's diseaseand ulcerative colitis, proliferative lymphocytic diseases, such asleukemias (e.g. chronic lymphocytic leukemia; CLL) (see Mentz et al.,Blood 88, pp. 2172-2182 (1996)), and inflammatory dermatoses, such asatopic dermatitis, psoriasis, or urticaria.

[0115] The compounds of the present invention also are useful in thetreatment of obesity, alone or in combination with a PDE3 inhibitor, andin the treatment and prevention of nephropathy in Type 2 diabetes (seeMora et al., New England Journal of Medicine, 342, p. 441 (2000)). PDE3inhibitors are known to persons skilled in the art.

[0116] Other examples of such diseases or related conditions includecardiomyopathies, such as congestive heart failure, pyrexia, cachexia,cachexia secondary to infection or malignancy, cachexia secondary toacquired immune deficiency syndrome (AIDS), ARC (AIDS-related complex),cerebral malaria, osteoporosis and bone resorption diseases, and feverand myalgias due to infection. In addition, the compounds of the presentinvention are useful in the treatment of erectile dysfunction,especially vasculogenic impotence (Doherty, Jr. et al. U.S. Pat. No.6,127,363), diabetes insipidus and central nervous system disorders,such as depression and multi-infarct dementia.

[0117] Compounds of the present invention also have utility outside ofthat typically known as therapeutic. For example, the present compoundscan function as organ transplant preservatives (see Pinsky et al., J.Clin. Invest., 92, pp. 2994-3002 (1993)) as well.

[0118] Selective PDE4 inhibitors also can be useful in the treatment oferectile dysfunction, especially vasculogenic impotence (Doherty, Jr. etal. U.S. Pat. No. 6,127,363), diabetes insipidus (Kidney Int., 37, p.362, (1990); Kidney Int., 35, p. 494, (1989)), and central nervoussystem disorders, such as multiinfarct dementia (Nicholson,Psychopharmacology, 101, p. 147 (1990)), depression (Eckman et al.,Curr. Ther. Res., 43, p. 291 (1988)), anxiety and stress responses(Neuropharmacology, 38, p. 1831 (1991)), cerebral ischemia (Eur. J.Pharmacol., 272, p. 107 (1995)), tardive dyskinesia (J. Clin.Pharmocol., 16, p. 304 (1976)), Parkinson's disease (see Neurology, 25,p. 722 (1975); Clin. Exp. Pharmacol, Physiol., 26, p. 421 (1999)), andpremenstrual syndrome. With respect to depression, PDE4-selectiveinhibitors show efficacy in a variety of animal models of depressionsuch as the “behavioral despair” or Porsolt tests (Eur. J. Pharmacol.,47, p. 379 (1978); Eur. J. Pharmacol., 57, p. 431 (1979);Antidepressants: neurochemical, behavioral and clinical prospectives,Enna, Malick, and Richelson, eds., Raven Press, p. 121 (1981)), and the“tail suspension test” (Psychopharmacology, 85, p. 367 (1985)). Recentresearch findings show that chronic in vivo treatment by a variety ofantidepressants increase the brain-derived expression of PDE4 (J.Neuroscience, 19, p. 610 (1999)). Therefore, a selective PDE4 inhibitorcan be used alone or in conjunction with a second therapeutic agent in atreatment for the four major classes of antidepressants:electroconvulsive procedures, monoamine oxidase inhibitors, andselective reuptake inhibitors of serotonin or norepinephrine. SelectivePDE4 inhibitors also can be useful in applications that modulatebronchodilatory activity via direct action on bronchial smooth musclecells for the treatment of asthma.

[0119] The selective PDE4 inhibitors of the present invention also canbe used in the treatment of infertility in both females and males. Thepresent PDE4 inhibitors elevate cAMP levels within granulosa cells, andthereby enhance gonadotropin induction of ovulation and oocytematuration (Tsafriri et al., Dev. Biol., 178, pp. 393-402 (1996)).Furthermore, the present PDE4 inhibitors can be used in treatments forinfertile couples having abnormal semen parameters by enhancing spermmotility without affecting the acrosome reaction (see Fosch et al., Hum.Reprod., 13, pp. 1248-1254 (1998)).

[0120] Compounds and pharmaceutical compositions suitable for use in thepresent invention include those wherein the active ingredient isadministered to a mammal in an effective amount to achieve its intendedpurpose. More specifically, a “therapeutically effective amount” meansan amount effective to prevent development of, or to alleviate theexisting symptoms of, the subject being treated. Determination of theeffective amounts is well within the capability of those skilled in theart, especially in light of the detailed disclosure provided herein.

[0121] The term “mammal” as used herein includes males and females, andencompasses humans, domestic animals (e.g., cats, dogs), livestock(e.g., cattle, horses, swine), and wildlife (e.g., primates, large cats,zoo specimens).

[0122] A “therapeutically effective dose” refers to that amount of thecompound that results in achieving the desired effect. Toxicity andtherapeutic efficacy of such compounds can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index, which is expressed as the ratio between LD₅₀ andED₅₀. Compounds which exhibit high therapeutic indices are preferred.The data obtained from such data can be used in formulating a dosagerange for use in humans. The dosage of such compounds preferably lieswithin a range of circulating concentrations that include the ED₅₀ withlittle or no toxicity. The dosage can vary within this range dependingupon the dosage form employed, and the route of administration utilized.

[0123] The exact formulation, route of administration, and dosage can bechosen by the individual physician in view of the patient's condition.Dosage amount and interval can be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain thetherapeutic effects.

[0124] As appreciated by persons skilled in the art, reference herein totreatment extends to prophylaxis, as well as to treatment of establisheddiseases or symptoms. It is further appreciated that the amount of acompound of the invention required for use in treatment varies with thenature of the condition being treated, and with the age and thecondition of the patient, and is ultimately determined by the attendantphysician or veterinarian. In general, however, doses employed for adulthuman treatment typically are in the range of 0.001 mg/kg to about 100mg/kg per day. The desired dose can be conveniently administered in asingle dose, or as multiple doses administered at appropriate intervals,for example as two, three, four or more subdoses per day. In practice,the physician determines the actual dosing regimen which is mostsuitable for an individual patient, and the dosage varies with the age,weight, and response of the particular patient. The above dosages areexemplary of the average case, but there can be individual instances inwhich higher or lower dosages are merited, and such are within the scopeof the present invention.

[0125] Formulations of the present invention can be administered in astandard manner for the treatment of the indicated diseases, such asorally, parenterally, transmucosally (e.g., sublingually or via buccaladministration), topically, transdermally, rectally, via inhalation(e.g., nasal or deep lung inhalation). Parenteral administrationincludes, but is not limited to intravenous, intraarterial,intraperitoneal, subcutaneous, intramuscular, intrathecal, andintraarticular. Parenteral administration also can be accomplished usinga high pressure technique, like POWDERJECT™.

[0126] For buccal administration, the composition can be in the form oftablets or lozenges formulated in conventional manner. For example,tablets and capsules for oral administration can contain conventionalexcipients such as binding agents (for example, syrup, accacia, gelatin,sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone),fillers (for example, lactose, sugar, microcrystalline, cellulose,maize-starch, calcium phosphate or sorbitol), lubricants (for example,magnesium, stearate, stearic acid, talc, polyethylene glycol or silica),disintegrants (for example, potato starch or sodium starch glycollate),or wetting agents (for example, sodium lauryl sulfate). The tablets canbe coated according to methods well known in the art.

[0127] Alternatively, the compounds of the present invention can beincorporated into oral liquid preparations such as aqueous or oilysuspensions, solutions, emulsions, syrups, or elixirs, for example.Moreover, formulations containing these compounds can be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations can contain conventional additives, suchas suspending agents, such as sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose,hydroxypropylmethylcellulose, carboxymethyl cellulose, aluminum stearategel, and hydrogenated edible fats; emulsifying agents, such as lecithin,sorbitan monooleate, or acacia; nonaqueous vehicles (which can includeedible oils), such as almond oil, fractionated coconut oil, oily esters,propylene glycol, and ethyl alcohol; and preservatives, such as methylor propyl p-hydroxybenzoate and sorbic acid.

[0128] Such preparations also can be formulated as suppositories, e.g.,containing conventional suppository bases, such as cocoa butter or otherglycerides. Compositions for inhalation typically can be provided in theform of a solution, suspension, or emulsion that can be administered asa dry powder or in the form of an aerosol using a conventionalpropellant, such as dichlorodifluoromethane or trichlorofluoromethane.Typical topical and transdermal formulations comprise conventionalaqueous or nonaqueous vehicles, such as eye drops, creams, ointments,lotions, and pastes, or are in the form of a medicated plaster, patch,or membrane.

[0129] Additionally, compositions of the present invention can beformulated for parenteral administration by injection or continuousinfusion. Formulations for injection can be in the form of suspensions,solutions, or emulsions in oily or aqueous vehicles, and can containformulation agents, such as suspending, stabilizing, and/or dispersingagents. Alternatively, the active ingredient can be in powder form forconstitution with a suitable vehicle (e.g., sterile, pyrogen-free water)before use.

[0130] A composition in accordance with the present invention also canbe formulated as a depot preparation. Such long acting formulations canbe administered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. Accordingly, thecompounds of the invention can be formulated with suitable polymeric orhydrophobic materials (e.g., an emulsion in an acceptable oil), ionexchange resins, or as sparingly soluble derivatives (e.g., a sparinglysoluble salt).

[0131] For veterinary use, a compound of formula (II), or nontoxic saltsthereof, is administered as a suitably acceptable formulation inaccordance with normal veterinary practice. The veterinarian can readilydetermine the dosing regimen and route of administration that is mostappropriate for a particular animal.

[0132] Thus, the invention provides in a further aspect a pharmaceuticalcomposition comprising a compound of the formula (II), together with apharmaceutically acceptable diluent or carrier therefor. There isfurther provided by the present invention a process of preparing apharmaceutical composition comprising a compound of formula (II), whichprocess comprises mixing a compound of formula (II), together with apharmaceutically acceptable diluent or carrier therefor.

[0133] Specific, nonlimiting examples of compounds of structural formula(II) are provided below, the synthesis of which were performed inaccordance with the procedures set forth below.

[0134] Generally, compounds of structural formula. (II) can be preparedaccording to the following synthetic schemes. In each scheme describedbelow, it is understood in the art that protecting groups can beemployed where necessary in accordance with general principles ofsynthetic chemistry. These protecting groups are removed in the finalsteps of the synthesis under basic, acidic, or hydrogenolytic conditionswhich are readily apparent to those skilled in the art. By employingappropriate manipulation and protection of any chemical functionalities,synthesis of compounds of structural formula (II) not specifically setforth herein can be accomplished by methods analogous to the schemes setforth below.

[0135] Unless otherwise noted, all starting materials were obtained fromcommercial suppliers and used without further purification. Allreactions and chromatography fractions were analyzed by thinlayerchromatography on 250-mm silica gel plates, visualized with UV(ultraviolet) light I₂ (iodine) stain. Products and intermediates werepurified by flash chromatography, or reverse-phase HPLC.

[0136] The compounds of general structural formula (II) can be prepared,for example, by first reacting a disubstituted benzaldehyde (1) with2-butanone, then following the reaction scheme illustrated below. Othersynthetic routes also are known and available to persons skilled in theart. For example, see Feldman et al. U.S. Pat. No. 5,665,754,incorporated herein by reference, for various individual reactions, andthe synthetic methods disclosed in the Intermediates and Examplespresented hereafter.

[0137] The above reaction scheme provides a compound (5) of structuralformula (II), wherein R¹ and R² are determined by the startingbenzaldehyde, R³ is C(═O)OCH₃, R⁴ is hydrogen, R⁵ is methyl, R⁶ ishydrogen, and R⁷ is methyl, and R¹⁰ is hydrogen. Proper selection ofstarting materials, or performing conversion reactions on compound (5),provide compounds of general structural formula (II) having otherrecited R¹ through R⁷ and R¹⁰ substituents.

[0138] The following illustrates the synthesis of various intermediatesand compounds of structural formula (II). The following examples areprovided for illustration and should not be construed as limiting.

[0139] In the structures herein, for a bond lacking a substituent, thesubstituent is methyl, for example:

[0140] Where no substituent is indicated as attached to a carbon or anitrogen atom, it is understood that the carbon atom contains theappropriate number of hydrogen atoms.

[0141] Abbreviations which are well known to one of ordinary skill inthe art also are used, e.g., “Me” for methyl, “OMs” for mesylate, “Ph”for phenyl, “CH₂Cl₂” for methylene chloride, “NaOH” for sodiumhydroxide, “EtOAc” for ethyl acetate, “NH₄OH” for ammonium hydroxide,“MeOH” for methanol, “LiOH” for lithium hydroxide, “CsCO₃” for cesiumcarbonate, “H₂” for hydrogen gas, “TFA” for trifluoroacetic acid, “OAc”for acetate, “Ac” for acetyl, “t-Bu” for tertiary butyl, “sat.” forsaturated, “h” for hour, “gm” for gram”, “mmol” for millimole, “eq” forequivalent, “M” for molar, and “N” for normal.

[0142] General Synthesis for Cyclopentyl Series:

[0143] General Synthesis for Indanyl Series:

[0144] General Synthesis Varying R¹ Substituents:

Intermediate 1 3-Cyclopropylmethoxy-4-methoxybenzaldehyde

[0145] A solution of 3-hydroxy-4-methoxybenzaldehyde (400 g, 2.63mole)and bromomethylcyclopropane (426 g, 3.2 mole) in 1 Ldimethylformamide (DMF) was stirred with potassium carbonate (K₂CO₃)(483 g, 3.5 mole) at 55° C. for 3.5 h. Then, 1 L of water was added, themixture chilled on ice, and Intermediate 1 filtered as a white solid,(535 g, 99%). m/z 207 (MH⁺).

Intermediate 2 3-(Indan-2-yloxy)-4-methoxybenzaldehyde

[0146] Mitsunobu Procedure

[0147] A solution of 3-hydroxy-4-methoxybenzaldehyde (15.2 g, 100 mmol,1 eq), 2-indanol (12.1 g, 90 mmol, 0.9 eq), and triphenylphosphine (26.2g, 100 mmol, 1 eq) in dry THF (300 mL) was treated dropwise withdiisopropylazodicarboxylate (DIAC) (19.6 mL, 100 mmol, 1 eq). Thereaction mixture was stirred at reflux for 16 h, then cooled and dilutedwith diethyl ether (500 mL). The solution was washed with water (2×150mL), 1 M NaOH (4×125 mL), and saturated sodium chloride (NaCl) (2×100mL), dried with sodium sulfate (Na₂SO₄), and concentrated to a syrupthat solidified upon standing. The solid was suspended in Et₂O (350 mL)and stirred overnight to provide small particles. The solid wascollected by vacuum filtration and recrystallized from ethanol/water(21.4 g). The ethereal filtrate was concentrated and purified by flashchromatography (silica gel, 7.5×36 cm Biotage KP-Sil column, eluted with25% EtOAc in heptane) to yield an additional 5 g of Intermediate 2.

[0148]¹H NMR (300 MHz, CDCl₃) δ: 9.86 (s, 1H), 7.49-7.44 (m, 2H),7.25-7.16 (m, 4H), 6.97 (d, J=8.7 Hz, 1H), 5.29-5.22 (m, 1H), 3.89 (s,1H), 3.45 (dd, J=16.7, 6.6 Hz, 2H), 3.24 (dd, J=16.7, 3.6 Hz, 2H).^(13C)NMR (75 MHz, CDCl₃) δ: 190.9, 155.5, 147.9, 140.4, 130.0, 126.9,126.8, 124.7, 112.1, 111.0, 78.9, 56.1, 39.7.

Intermediate 3 3-(tert-Butoxy)-4-methoxybenzaldehyde

[0149] To a stirred solution of isovanillin (30.4 gm, 200 mmol) inCH₂Cl₂ (200 mL) at room temperature under a nitrogen blanket was added(2-aza-1-(tert-butoxy)-3-methylbut-1-enyl)(methylethyl)amine (crude 40mL, about 200 mmol) as an alkylating agent. Every 2 hours, another molarequivalent of the alkylating agent was added until 5 equivalents totalwere added. The reaction was allowed to stir another 16 hours. TLC in3/7 EtOAc/hexane indicated the reaction was approximately 80% tocomplete. The mixture was diluted with CH₂Cl₂ (500 mL) and washed with3M NaOH (4×300 mL) to remove unreacted isovanillin. The organics weredried over magnesium sulfate (MgSO₄), filtered, and concentrated invacuo to a crude brown oil, which was flash chromatographed in 3/1hexane/EtOAc and dried in vacuo to provide pure Intermediate 3 (22.6 gm,54%).

[0150]¹H-NMR (CDCl₃, 400 MHz) δ: 9.84 (s, 1H), 7.60 (d, 1H), 7.55 (s,1H), 7.00 (d, 1H), 3.86 (s, 3H), 1.39 (s, 9H).

Intermediate 4 (2E)-3-(3-tert-Butoxy-4-methoxyphenyl)-2-methyl-acrylicacid ethyl ester

[0151] Horner-Emmons Procedure

[0152] To a stirred solution of triethyl 2-phosphonopropionate (25.6 mL,119.4 mmol) in THF (120 mL) at 0° C. under a nitrogen blanket was addedlithium hexamethyldisilylamide (1M in THF, 114 mL, 114 mmol) dropwise bysyringe. After 30 minutes, a solution of Intermediate 3 (22.6 gm, 108mmol) in THF (40 mL) was added by cannulation. After 2 hours at 0° C.,TLC in 4/1 hexane/EtOAc showed complete reaction. The reaction waspartially concentrated by rotary evaporator and partitioned betweenEtOAc (500 mL) and water (500 mL). The organics were washed withsaturated NaCl (500 mL), dried (MgSO₄), filtered, and concentrated invacuo. The crude product was flash chromatographed in 9/1 hexane/EtOActo provide, after concentration in vacuo, Intermediate 4 (34.1 gm, 98%).

[0153]¹H-NMR (CDCl₃, 400 MHz) δ: 7.60 (s,. 1H), 7.16 (d, 1H), 7.12 (s,1H), 6.91 (d, 1H), 3.83 (s, 3H), 2.13 (s, 3H), 1.37 (s, 9H).

Intermediate 5 (2E)-3-(3-tert-Butoxy-4-methoxyphenyl)-2-methyl-acrylicacid

[0154] Lithium Hydroxide Hydrolysis Procedure

[0155] To a stirred solution of Intermediate 4 (34.1 gm, 116 mmol) indioxane (116 mL) at room temperature under a nitrogen blanket was addeda solution of LiOH monohydrate (5.87 gm, 140 mmol) in water (116 mL).The reaction was heated at 80° C. for 2 hours, then allowed to cool toroom temperature. The reaction then was partitioned between EtOAc (400mL) and 1M phosphoric acid (H₃PO₄) (400 mL). The organics were isolated,washed with H₂O (400 mL) and saturated NaCl (400 mL), dried (MgSO₄),filtered, and concentrated in vacuo to provide Intermediate 5 as a whitesolid (28.2 gm, 92%).

[0156]¹H-NMR (CDCl₃, 400 MHz) δ: 7.66 (s, 1H), 7.20 (d, 1H), 7.18 (s,1H), 6.92 (d, 1H), 3.83 (s, 3H), 2.16 (s, 3H), 1.38 (s, 9H).

Intermediate 6(E)-4-(3-Benzyloxy-4-methoxyphenyl)-3-methylbut-3-en-2-one

[0157] Acid-Catalyzed Aldol Condensation Procedure

[0158] A solution of commercially available3-benzyloxy-4-methoxybenzaldehyde (34 g, 0.14 mol, 1 eq) and 2-butanone(50 mL, 0.56 mol, 4 eq) in dry THF (50 mL) was cooled to −4° C. Hydrogenchloride gas was passed through the well-stirred solution for severalminutes, and the reaction mixture was capped and stored at −4° C. for 16h. The mixture was poured into a well stirred solution of ice-coldsaturated sodium bicarbonate (NaHCO₃) (about 2 L). If necessary, the pHwas adjusted to >7 with sat. NaHCO₃, and the mixture was extracted withEtOAc (3×300 mL).

[0159] The EtOAc layer was washed with NaHCO₃ (2×200 mL), water (2×200mL), and saturated NaCl (2×200 mL), dried with Na₂SO₄, and concentratedto a syrup. Crude mixture was purified by flash chromatography (silicagel, 7.5×36 cm Biotage KP-Sil column, eluted with 25% EtOAc in heptane)to yield Intermediate 6 (29.1 g, 70%).

[0160]¹H NMR (300 MHz, CDCl₃) δ: 7.46-7.27 (m, 6H), 7.06-6.91 (m, 3H),3.93 (s, 3H), 2.41 (s, 3H), 1.92 (d, J=1.1 Hz, 3H).

Intermediate 7(E)-4-[3-(Indan-2-yloxy)-4-methoxyphenyl]-3-methyl-but-3-en-2-one

[0161] Prepared from Intermediate 2 by the acid-catalyzed aldolcondensation procedure of Intermediate 6. LRMS (Electrospray, positive):Da/e 323.4 (m+l).

Intermediate 8 (E)-4-(3-Bromo-4-methoxyphenyl)-3-methylbut-3-en-2-one

[0162] Prepared from 3-bromo-4-methoxybenzaldehyde by the acid-catalyzedaldol condensation procedure of Intermediate 6.

[0163]¹H NMR (300 MHz, CDCl₃) δ: 7.66 (d, J=2.0 Hz, 1H), 7.36-7.41 (m,2H), 6.94 (d, J=8.6 Hz, 1H), 3.94 (s, 3H), 2.45 (s, 3H), 2.06 (d, J=1.1Hz, 3H).

Intermediate 9(E)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-but-3-en-2-one

[0164] Prepared from Intermediate 1 by the acid-catalyzed aldolcondensation procedure of Intermediate 6.

[0165]¹H NMR (300 MHz, CDCl₃) δ: 7.45 (br s, 1H), 7.05-6.99 (m, 2H),6.90 (d, J=8.26 Hz, 1H), 4.81-4.75, m, 1H), 3.89 (s, 3H), 2.46 (s, 3H),2.09 (d, J=1.1 Hz, 3H), 1.98-1.79 (m, 6H), 1.66-1.60 (m, 2H).

Intermediate 10 Ethyl(2E)-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylprop-2-enoate

[0166] Prepared from commercially available3-cyclopentyl-oxy-4-methoxybenzaldehyde by the Horner-Emmons procedureof Intermediate 4 to yield a brown liquid (68.4 g, 100%).

[0167]¹H NMR (400 MHz, CDCl₃) δ: 7.64 (s, 1H), 7.01-6.96 (c, 2H), 6.87(m, 1H), 4.77 (m, 1H), 4.26 (q, 2H), 3.87 (s, 3H), 2.14 (s, 3H),1.81-1.96 (c, 6H), 1.59-1.63 (c, 2H), 1.34 (t, 3H). LRMS (Electrospray,positive): Da/e 305.3 (m+1).

Intermediate 11(2E)-3-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methyl-prop-2-enoic acid

[0168] Intermediate 10 (68.4 g; 225 mmol)was hydrolyzed by the LiOHhydrolysis procedure of Intermediate 5 to provide Intermediate 11 as anorange solid (55 g, 88%).

[0169]¹H NMR (400 MHz, CDCl₃) δ: 7.76 (s, 1H), 7.06-7.00 (c, 2H), 6.89(m, 1H), 4.78 (m, 1H), 3.88 (s, 3H), 2.17 (s, 3H), 1.97-1.83 (c, 6H),1.64-1.61 (c, 2H). LRMS (Electrospray, negative): Da/e 275.3 (M−1).

Intermediate 12(2E)-3-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methyl-prop-2-enoyl chloride

[0170] Acid Chloride Procedure

[0171] To a cooled (0° C.), stirred slurry of Intermediate 11 (55 g, 199mmol) in anhydrous CH₂Cl₂ (400 mL) was added a solution of oxalylchloride in CH₂Cl₂ (109 mL of 2.0 M, 218 mmol, 1.1 eq.) via syringeunder a calcium chloride-dried atmosphere over 10 minutes. Vigorousbubbling was observed. The resulting dark solution was allowed to stirat 0° C. for 15 minutes, then a catalytic amount of DMF was added viasyringe (0.3 mL). The resulting solution was stirred at 0° C. for 0.5hours while the bubbling subsided, then allowed to warm to roomtemperature and stir overnight (17 hours). The reaction was diluted withEtOAc (500 mL) and was carefully quenched with water (250 mL). Aftervigorously stirring for 1 hour, the layers were separated and theorganic layer was washed with water (400 mL) and brine (400 mL), thendried (MgSO₄), filtered, and concentrated in vacuo to provideIntermediate 12 as a brown solid (57.5 g, 98%).

[0172]¹H NMR (400 MHz, CDCl₃) δ: 7.98 (s, 1H), 7.11-7.02 (c, 2H), 6.92(m, 1H), 4.79 (m, 1H), 3.90 (s, 3H), 2.22 (s, 3H), 2.01-1.82 (c, 6H),1.68-1.62 (c, 2H).

Intermediate 13 Ethyl(2E)-3-(3-indan-2-yloxy-4-methoxyphenyl)-2-methylprop-2-enoate

[0173] Prepared via the Horner Emmons procedure of Intermediate 4 fromIntermediate 2.

[0174]¹H NMR (400 MHz, CDCl₃) δ: 7.64 (d, 1H), 7.28-7.17 (m, 4H), 7.06(dd, 1H), 7.03 (d, 1H), 6.90 (d, 1H), 5.20 (c, 1H), 4.28 (q, 2H), 3.85(s, 3H), 3.39 (dd, 2H), 3.26 (dd, 2H), 2.16 (d, 3H), 1.36 (t, 3H).

Intermediate 14(2E)-3-(3-Indan-2-yloxy-4-methoxyphenyl)-2-methyl-prop-2-enoic acid

[0175] Prepared from Intermediate 13 via the LiOH hydrolysis procedureof Intermediate 5.

[0176]¹H NMR (D₆ DMSO, 400 MHz) δ: 7.56 (s, 1H), 7.25-7.11 (m, 5H), 7.06(d, 1H), 6.99 (d, 1H), 5.22 (c, 1H), 3.71 (s, 3H), 3.34 (dd, 2H), 3.03(d, 2H), 2.06 (s, 3H).

Intermediate 15(2E)-3-(3-Indan-2-yloxy-4-methoxyphenyl)-2-methyl-prop-2-enoyl chloride

[0177] Prepared from Intermediate 14 via the acid chloride procedure ofIntermediate 12.

[0178]¹H NMR (400 MHz, CDCl₃) δ: 8.01 (s, 1H), 7.29-6.93 (m, 7H), 5.23(c, 1H), 3.89 (s, 3H), 3.42 (dd, 2H), 3.28 (dd, 2H), 2.26 (s, 3H).

Intermediate 163-[(2E)-3-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylprop-2-enoyl](4R)-4-phenyl-1,3-oxazolidin-2-one

[0179] Oxazolidinone Acylation Procedure

[0180] To a cooled (−78° C.), overhead, mechanically stirred solution ofR-phenyl oxazolidinone (10.0 g, 61.3 mmol) in dry tetrahydrofuran (400mL) was added a solution of n-butyllithium in hexanes (27 mL of 2.5 M,1.1 eq.) via syringe under a nitrogen atmosphere. The resulting solutionwas allowed to stir at −78° C. for 0.8 hours, then a solution ofIntermediate 12 (19.9 g, 67.4 mmol, 1.1 eq.) in THF (100 mL) was addedvia cannula. After stirring at −78° C. for 15 minutes, the reaction wasallowed to slowly warm to 0° C. over 40 minutes during which time thereaction became a thick slurry. After stirring at 0° C. for 2.5 hours,the reaction was quenched with saturated, aqueous ammonium chloride(NH₄Cl) (300 mL) and the bulk of the THF was removed at reducedpressure. The residue then was extracted with chloroform (CHCl₃) (3×700mL) and the combined organic layers were washed with water (300 mL) andbrine (300 mL), then dried (MgSO₄), filtered, and concentrated in vacuoto provide about 33 g of a light orange solid. The material wassuspended in 10% EtOAc in hexane (1.2 L) and vigorously stirredovernight. The resulting fine powdery solids were collected on a Buchnerfunnel with suction, then dried in vacuo to provide Intermediate 16 as atan powder (21.8 g, 88%).

[0181]¹H NMR (400 MHz, CDCl₃) δ: 7.41-7.37 (c, 5H), 7.06 (s, 1H),7.01-6.97 (c, 2H), 6.86 (m, 1H), 5.54 (t, 1H), 4.77-4.73 (c, 2H), 4.29(t, 1H), 3.87 (s, 3H), 2.17 (s, 3H), 1.97-1.82 (c, 6H), 1.62-1.56 (c,2H).

Intermediate 173-[(2E)-3-(3-Indan-2-yloxy-4-methoxyphenyl)-2-methylprop-2-enoyl](4R)-4-phenyl-1,3-oxazolidin-2-one

[0182] Prepared from Intermediate 15 via the oxazolidinone acylationprocedure of Intermediate 16.

[0183]¹H NMR (400 MHz, CDCl₃) δ: 7.43-7.33 (m, 5H), 7.25-7.16 (m, 4H),7.07-7.03 (m, 2H), 6.89 (d, 1H), 5.54 (dd. 1H), 5.19 (c, 1H), 4.74 (t,1H), 4.28 (dd, 1H), 3.84 (s, 3H), 3.38 (dd, 2H), 3.24 (ddd, 2H), 2.19(d, 3H).

Intermediate 18 Ethyl(2E)-3-[4-methoxy-3-(phenylmethoxy)phenyl]-2-methylprop-2-enoate

[0184] Prepared from 3-benzyloxy-4-methoxybenzaldehyde via the HornerEmmons procedure of Intermediate 4.

[0185]¹H NMR (400 MHz, CDCl₃) δ: 7.56 (s, 1H), 7.44 (t, 2H), 7.36 (t,2H), 7.30 (t, 1H), 7.01 (dd, 1H), 6.95 (d, 1H), 6.90 (d, 1H), 5.18 (s,2H), 4.24 (q, 2H), 3.92 (s, 3H), 1.98 (d, 3H), 1.33 (t, 3H).

Intermediate 19(2E)-3-[4-Methoxy-3-(phenylmethoxy)phenyl]-2-methylprop-2-enoic acid

[0186] Prepared from Intermediate 18 via the LiOH hydrolysis procedureof Intermediate 5 and used without characterization.

Intermediate 20(2E)-3-[4-Methoxy-3-(phenylmethoxy)phenyl]-2-methyl-prop-2-enoylchloride

[0187] Prepared from Intermediate 19 via the acid chloride procedure ofIntermediate 12.

[0188]¹H NMR (400 MHz, CDCl₃) δ: 7.91 (s, 1H), 7.47-7.29 (m, 5H), 7.10(dd, 1H), 7.00 (d, 1H), 6.95 (d, 1H), 5.20 (s, 2H), 3.95 (s, 3H), 2.04(s, 3H).

Intermediate 213-{(2E)-3-[4-Methoxy-3-(phenylmethoxy)phenyl]-2-methylprop-2-enoyl}(4R)-4-phenyl-1,3-oxazolidin-2-one

[0189] Prepared from Intermediate 19 via the oxazolidinone acylationprocedure of Intermediate 16.

[0190]¹H NMR (400 MHz, CDCl₃) δ: 7.44-7.29 (m, 11H), 7.03-6.89 (m, 3H),5.52 (dd, 1H), 5.17 (s, 2H), 4.73 (dt, 1H), 4.27 (dd, 1H), 3.91 (s, 3H),2.00 (s, 3H).

Intermediate 22(2E)-3-[3-(3-tert-Butoxy-4-methoxyphenyl)-2-methyl-acryloyl]-4-R-phenyloxazolidin-2-one

[0191] Prepared from Intermediate 5 (25.7 gm, 97.2 mmol) via theoxazolidinone acylation procedure of Intermediate 16 to provideIntermediate 22 as an off-white solid (39.8 gm, quantitative yield).

[0192]¹H-NMR (CDCl₃, 400 MHz) δ: 7.42-7-33 (m, 5H), 7.16 (d, 1H), 7.02(s, 1H), 6.87 (d, 1H), 5.55 (dd, 1H), 4.73 (dd, 1H), 4.26 (dd, 1H), 3.81(s, 3H), 2.16 (s, 3H), 1.38 (s, 9H).

Intermediate 23trans-(±)-1-[1-Benzyl-4-(3-benzyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethanone

[0193] Azomethine Ylide Cyclization

[0194] A solution of Intermediate 6 (15 g, 50.6 mmol, 1 eq) andN-(methoxymethyl)-N-(trimethysilylmethyl)benzyl-amine (11.9 g, 50.6mmol, 1 eq) in CH₂Cl₂ (85 mL) at 0° C. was treated dropwise with asolution of TFA (1 M in CH₂Cl₂, 5 mL, 5.1 mmol, 0.1 eq). After stirringat the 0° C. for 30 min., the reaction mixture was stirred at roomtemperature for 16 h. The solution was treated with additionalN-(methoxymethyl)-N-(trimethysilylmethyl)benzylamine (6 g, 25.3 mmol,0.5 eq), stirred 1 h at room temperature, and treated for a third timewith N-(methoxymethyl)-N-(trimethysilylmethyl)benzylamine (6 g, 25.3mmol, 0.5 eq). The reaction mixture was concentrated, and the residuewas dissolved in EtOAc (500 mL). The solution was washed with 1 N HCl(2×60 mL with 10 mL sat. NaCl added), water (250 mL), 1 M NaOH (250 mL),water (250 mL), sat. NaCl (2×100 mL), dried with Na₂SO₄, andconcentrated in vacuo. The residue was purified by flash chromatography(silica gel, 7.5×36 cm Biotage KP-Sil column, eluted with 5-10% diethylether in dichloromethane) to yield Intermediate 23 as a light yellowsyrup (17.4 g, 80%).

[0195]¹H NMR (300 MHz, CDCl₃) δ: 7.44-7.22 (m, 10 H), 6.81-6.72 (m, 3H),5.14 (s, 2H), 3.86 (s, 3H), 3.72-3.67 (m, 2H), 3,58 (d, J=13.0 Hz, 1H),3.08 (d, J=9.7 Hz, 1H), 2.99 (dd, J=8.9, 7.8 Hz, 1H), 2.74 (dd, J=9.1,7.4 Hz, 1H), 2.33 (d, J=9.7 Hz, 1H), 2.15 (s, 3H), 0.68 (s, 3H). ¹³C NMR(75 MHz, CDCl₃) δ: 211.3, 148.4, 147.4, 139.2, 137.2, 132.7, 128.51,128.50, 128.3, 127.8, 127.4, 127.0, 121.6, 115.5, 111.2, 71.0, 63.8,60.0, 59.5, 57.9, 56.0, 47.7, 25.6, 20.6.

Intermediate 24trans-(±)-1-{1-Benzyl-4-[3-(indan-2-yloxy)-4-methoxyphenyl]-3-methylpyrrolidin-3-yl}ethanone

[0196] Prepared from Intermediate 7 by the azomethine cyclizationprocedure of Intermediate 23.

[0197]¹H NMR (300 MHz, CDCl₃) δ: 7.38-7.16 (m, 9 H), 6.88 (br s, 1H),6.78 (br s, 2H), 5.18-5.13 (m, 1H), 3.82-3.73 (m, 2H), 3.79 (s, 3H),3.60 (d, J=13.0 Hz, 1H), 3.41-3.17 (m, 4H), 3.14 (d, J=9.7 Hz, 1H), 3.05(t, J=8.3 Hz, 1H), 2.84 (t, J=8.3 Hz, 1H), 2.44 (d, J=9.7 Hz, 1H), 2.24(s, 3H), 0.86 (s, 3H).

Intermediate 25(±)-1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidine-3-carboxylicacid ethyl ester

[0198] Prepared from Intermediate 10 by the azomethine ylide cyclizationreaction of Intermediate 23 to yield an amber oil (16.7 g, 61% yield).

[0199]¹H NMR (300 MHz, CDCl₃) δ: 7.39-7.23 (m, 5H, aromatic), 6.91 (s,1H, aromatic), 6.78 (m, 2H, aromatic), 4.75 (m, 1H), 4.18 (q, 2H, OEt),3.86 (m, 1H), 3.81 (s, 3H, OCH₃), 3.75 (d, 1H, J=13.2 Hz), 3.62 (d, 1H,J=13.2 Hz) 3.20 (d, 1H, J=9.5 Hz) 3.01 (m, 1H), 2.91 (m, 1H), 2.51 (d,1H, J=9.5 Hz), 1.93-1.58 (m, 8H, cyclopentyl), 1.28 (t, 3H, OEt), 0.9(s, 3H, CH₃).

Intermediate 26trans-(±)-1-[1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethanone

[0200] Prepared according to procedure set forth in U.S. Pat. No.5,665,754.

Intermediate 27(±)-[1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]methanol

[0201] To a magnetically stirred solution of Intermediate 25 (9.32g,21.3 mmol) in dry toluene (10 mL) at 0° C. was added diisobutylaluminumhydride (64 mL, 1.0M in CH₂Cl₂, 63.9 mmol). The mixture was stirred for30 minutes at 0° C., then at room temperature for 1 hour, and finallyquenched with MeOH (20 mL). A 1.0 N hydrochloric acid (HCl) solution(100 mL) then was added, and the mixture stirred another 30 minutes. Thephases were separated and the aqueous phase extracted with CH₂Cl₂ (2×20mL). The organic phases were washed with a saturated NH₄Cl solution,dried over anhydrous Na₂SO₄, then concentrated to afford a light yellowoil product (8.28g, 98% yield).

[0202]¹H NMR (300 MHz, CDCl₃) δ: 7.31-7.14 (m, 5H, aromatic), 6.78-6.71(m, 3H, aromatic), 4.76-4.73 (br. m, 1H), 3.79 (s, 3H, OCH₃), 3.71-3.55(m, 3H), 3.47-3.10 (m, 3H), 2.92 (d, 1H, J=9.2 Hz), 2.62 (m, 1H),3.35-2.33 (m, 2H), 1.89-1.58 (m, 8H, cyclopentyl), 0.52 (s, 3H, CH₃).

Intermediate 28(±)-1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidine-3-carboxaldehyde

[0203] A solution of oxalyl chloride (4.87 mL, 9.73 mmol) in dry CH₂Cl₂(20 mL) was chilled to −78° C. under a nitrogen blanket, and stirredwhile being treated with a solution of dimethyl sulfoxide (DMSO, 1.38mL, 19.5 mmol) in CH₂Cl₂ (5 mL). Gas evolution was observed. When theaddition was complete, the solution was stirred for 5 minutes, then asolution of Intermediate 27 (3.5 g, 8.85 mmol) in CH₂Cl₂ (10 mL) wasadded over a period of 10 minutes. The mixture was stirred for 30minutes, treated with triethylamine (Et₃N) (6.7 mL, 44.3 mmol), andallowed to warm to room temperature. Water was added to the mixture, andthe resulting phases separated. The aqueous phase was extracted withCH₂Cl₂ (2×50 mL). The combined organic phases were washed with brine,dried (Na₂SO₄) and concentrated to give an oily product (3.2 g, 92%).

[0204]¹H NMR (300 MHz, CDCl₃) δ: 9.63 (s, 1H, CHO), 7.34-7.21 (m, 5H,aromatic), 6.78-6.68 (m, 3H, aromatic), 4.73 (br. m, 1H), 3.80 (s, 3H,OCH₃), 3.78-3.61 (m, 3H), 3.18-3.11 (m, 2H), 2.86-2.81 (m, 1H),2.58-2.52 (m, 1H), 2.43-2.34 (m, 2H), 1.87-1.59 (m, 8H, cyclopentyl),0.74 (s, 3H, CH₃).

Intermediate 29(±)-1-[1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]-1-hydroxypropan-2-one

[0205] To a solution of ethyl vinyl ether (0.95 mL, 9.91 mmol) in dryTHF (4 mL) at −78° C. was added 1.7M t-butyllithium in pentane (5.25 mL,8.93 mmol), and the resulting solution was warmed to 0° C. The color ofthe solution changed from yellow to colorless. The resulting vinyl anionthen was cooled to −78° C., and a solution of Intermediate 28 (1.95 g,4.96 mmol) in THF (1.0 mL) was added dropwise. The resulting mixture wasstirred for 45 minutes, quenched with saturated NH₄Cl (15 mL), andextracted with Et₂O (3×30 mL). The combined organic extracts were driedover Na₂SO₄ and concentrated. The crude product was dissolved in Et₂Oand treated with concentrated sulfuric acid (H₂SO₄) in a separatoryfunnel while shaking vigorously. The Et₂O solution was washed with water(30 mL), with saturated NaHCO₃ (30 mL) solution, dried over Na₂SO₄, andconcentrated. The residue was purified by flash chromatography (silicagel, 20% EtOAc-hexanes) to provide Intermediate 29 as an orange oil(1.36 g, 62% yield).

[0206]¹H NMR (300 MHz, CDCl₃) δ: 7.34-7.27 (m, 5H, aromatic), 6.77-6.68(m, 3H, aromatic), 4.75-4.72 (br. m, 1H), 4.13-4.08 (m, 1H), 3.81 (s,3H, OCH₃), 3.79-3.57 (m, 3H), 3.26 (m, 1H), 2.99 (d, 1H, J=9.2 Hz),2.69-2.64 (m, 1H), 2.39 (d, 1H, J=9.2 Hz) 2.25 (s, 3H, OCH₃), 1.94-1.59(m, 8H, cyclopentyl), 0.69 (s, 3H, CH₃).

EXAMPLE 1(±)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-(1-hydroxy-1-methylethyl)-3-methylpyrrolidine-1-carboxylicacid methyl ester

[0207] To a 3.0 M solution of methylmagnesium bromide (0.6 mL, 1.8 mmol)in Et₂O at 0° C. was added a solution of Intermediate 36 (0.65 g, 1.73mmol) in dry THF (5 mL), dropwise via a syringe pump. The resultingmixture was stirred at 0° C. for 30 minutes, then at room temperaturefor 1 hour. The reaction mixture then was quenched with saturated NH₄Cl(15 mL) and extracted with Et₂O (2×10 mL). The combined organic extractswere dried over Na₂SO₄ and concentrated. The residue was purified byflash chromatography (silica gel, 20% EtOAc-hexanes, then 50%) toprovide Example 1 as an orange oil (0.37 g, 55%).

[0208]¹H NMR (300 MHz, CDCl₃) δ: 6.83-6.77 (m, 3H, aromatic), 4.75-4.74(br. m, 1H), 3.83 (s, 3H, OCH₃), 3.96-3.50 (m,4H), 3.73 (s, 3H, OCH₃),3.37-3.25 (m, 1H), 1.96-1.59 (m, 8H, cyclopentyl), 1.22 (s, 3H, CH₃),1.07 (s, 6H, CH₃).

Intermediate 302-[1-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]propan-2-ol

[0209] Intermediate 33 (0.992 g, 2.52 mmol) was dissolved in THF (7.5mL) and the solution was cooled to 0° C. Methylmagnesium iodide (3.0 Min ether, 2.52 mL, 7.6 mmol) was added and the reaction mixture wasstirred at 0° C. for 1.5 hours. Saturated NH₄Cl was added and thereaction mixture was concentrated in vacuo. The residue was diluted withEtOAc and the organic layer was washed three times with saturatedNaHCO₃, saturated NaCl, then dried over Na₂SO₄ and concentrated in vacuo(0.96 g, 93%).

[0210]¹H NMR (CDCl₃, 400 MHz) δ: 7.33-7.24 (m, 5H), 6.83-6.77 (m, 3H),3.86-3.74 (m, 7H), 3.68-3.59 (dd, 2H), 3.32 (dd, 1H), 3.24 (d, 1H), 2.48(dd, 1H), 2.16 (d, 1H), 1.35-1.28 (m, 1H), 1.21-1.18 (m, 5H), 0.66-0.60(m, 2H), 0.56 (s, 3H), 0.38-0.33 (m, 2H). LRMS (Electrospray, positive):Da/e 410.5 (m+1).

Intermediate 312-[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]propan-2-ol

[0211] Intermediate 30 (0.96 g, 2.3 mmol) was dissolved in methanol (10mL) and the solution was treated with Pearlman's catalyst (20% Pd(OH)₂on carbon, 200 mg) and ammonium formate (1.0 g, 15.8 mmol). The solutionwas heated to reflux for 6 hours. The catalyst was removed by filtrationand the solution was concentrated in vacuo. The residue was dissolved inEtOAc and washed three times with water, saturated NaCl, dried overNa₂SO₄ and concentrated in vacuo, (384 mg, 52%).

[0212]¹H NMR (CDCl₃, 400 MHz) δ: (6.83-6.79(m, 3H), 3.86-3.80 (m, 5H),3.75-3.66 (m, 2H), 3.57-3.51 (m, 2H), 3.22-3.17 (m, 1H), 2.78-2.67 (m,1H), 1.34-1.21 (m, 7H), 0.69 (s, 3H), 0.66-0.60 (m, 2H), 0.37-0.33 (m,2H). LRMS (Electrospray, positive): Da/e 320.3(m+1).

Intermediate 322-Benzyloxy-1-[4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(1-hydroxy-1-methylethyl)-3-(S)-methylpyrrolidin-1-yl]ethanone

[0213] Intermediate 31 (75 mg, 0.23 mmol) was dissolved in CH₂Cl₂ (1 mL)and the solution was treated with N,N-diisopropylethylamine (DIEA) (61μL, 0.35 mmol), then cooled to 0° C. Benzyloxyacetyl chloride (55.6 μL,0.23 mmol) was added, and the solution was stirred at 0° C. for 3 hours.The reaction mixture was diluted with CH₂Cl₂ and washed three times with1N HCl, once with water, three times with 6% NaHCO₃, then dried withNa₂SO₄ and concentrated in vacuo. The crude product (103 mg) waschromatographed with EtOAc/hexane (1:1) to provide Intermediate 32 (21mg, 19%).

[0214]¹H NMR (CDCl₃, 400 MHz) δ: 7.41-7.27 (m, 5H), 6.85-6.76 (m, 3H),4.66-4.61 (m, 2H), 4.13-4.07 (m, 2H), 3.94-3.59 (m, 7H), 3.53-3.47 (m,1H), 3.28-3.22 (m, 1H), 1.34-1.24 (m, 2H), 1.24-1.19 (m, 2H), 1.14-1.11(m, 2H), 1.07-0.98 (m, 6H), 0.66-0.59 (m, 2H), 0.36-0.31 (m, 2H). LRMS(Electrospray, positive): Da/e 468.3 (m+1).

EXAMPLE 21-[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(1-hydroxy-1-methylethyl)-3-(S)-methylpyrrolidin-1-yl]-2-hydroxyethanone

[0215] Intermediate 32 (21 mg, 45 μmol) was dissolved in ethanol (95%, 2mL) and treated with Pearlman's catalyst (20% Pd(OH)₂ on carbon, 20 mg).The solution was subjected to 1 atmosphere of H₂ for 20 hours. Thecatalyst was removed by filtration and concentrated in vacuo, to affordExample 2 (15 mg, 88%).

[0216]¹H NMR (CDCl₃, 400 MHz) δ: 6.87-6.80 (m, 3H), 4.20-4.09 (m, 2H),3.89-3.62 (m, 9H), 3.58-3.51 (m, 1H), 3.13-2.87 (m, 2H), 1.35-1.01 (m,10H), 0.67-0.61 (m, 2H), 0.39-0.33 (2H). LRMS (Electrospray, positive):Da/e 378.4 (m+1).

Intermediate 331-[1-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]ethanone

[0217] Oxalyl chloride (2.0M in CH₂Cl₂, 1.35 mL, 2.7 mmol) was added toCH₂Cl₂ (4 mL) and the solution was cooled to −60° C. A solution of DMSO(0.36 mL, 5.0 mmol) in CH₂Cl₂ (1.5 mL) was added slowly. This solutionwas stirred for 5 minutes, then Intermediate 66 (1.06 g, 2.7 mmol)dissolved in CH₂Cl₂ (7.5 mL) was added to the solution. The reaction wasstirred for 30 minutes at −60° C., then quenched with Et₃N (1.9 mL). Themixture was allowed to warm to room temperature, diluted with water, andafter stirring vigorously for several minutes, the layers wereseparated. The organic layer was washed three times with 1 N HCl, threetimes with 6% NaHCO₃ then dried over Na₂SO₄, and concentrated in vacuo.Intermediate 33 was recovered and used without purification, (0.992 g,93%)

[0218] LRMS (Electrospray, positive): Da/e 392.4 (m+1).

Intermediate 34trans-(±)-[3-Acetyl-4-(3-benzyloxy-4-methoxyphenyl)-3-methyl]pyrrolidine-1-carboxylicacid methyl ester

[0219] A solution of Intermediate 23 (17.4 g, 40.5 mmol, 1 eq) inacetonitrile (150 mL) was treated with methyl chloroformate (15.6 mL,202.5 mmol, 5 eq), then stirred at reflux 1 hour. The reaction mixturewas concentrated, and the residue was purified by flash chromatography(silica gel, 7.5×36 cm Biotage KP-Sil column, eluted with 50-60% EtOAcin heptane) to afford Intermediate 34 as a colorless syrup (13.7 g,85%).

[0220]¹H NMR (300 MHz, CDCl₃) δ: 7.42-7.27 (m, 5H), 6.82 (d, J=8.8 Hz,1H), 6.69 (br d, J=8.3 Hz, 1H), 6.63 (d, J=1.8 Hz, 1H), 5.15 (s, 2H),3.88 (s, 3H), 3.84 (dd, J=16.3, 11.0 Hz, 1H), 3.73 (br s, 3H), 3.24/3.12(2 d, J=11.31/11.0 Hz, 1H), 2.09/2.01 (2 s, 3H), 0.84 (s, 3H). ¹³C NMR(75 MHz, CDCl₃) δ: 210.0/209.8, 155.2, 149.0, 147.5, 137.0, 130.5/130.0,128.5, 127.8, 127.2/127.1, 121.2/121.0, 114.9/114.8, 111.5, 70.9,58.1/57.2, 55.9, 54.4/54.0, 52.5, 50.2/50.0, 48.4/48.0, 26.3, 17.5.

Intermediate 35trans-(±)-3-Acetyl-4-[3-(indan-2-yloxy)-4-methoxyphenyl]-3-methylpyrrolidine-1-carboxylicacid methyl ester

[0221] Prepared from Intermediate 24 by the methyl chloroformateprocedure of Intermediate 34.

[0222]¹H NMR (300 MHz, CDCl₃) δ: 7.24-7.16 (m, 4H), 6.82 (d, J=8.8 Hz,1H), 6.75-6.72 (m, 2H), 5.18-5.10 (m, 1H), 3.91 (t, J=11.2 Hz, 1H), 3.80(s, 3H), 3.77-3.65 (m, 3H), 3.74 (s, 3H), 3.42-3.16 (m, 5H), 2.17 (d,J=6.8 Hz, 3H), 1.04 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ: 210.1/209.9,155.3, 149.4, 146.9/146.8, 140.5/140.4, 130.5/130.0, 126.7, 124.7,121.3/121.1, 116.1/115.8, 111.9, 79.2, 58.2/57.4, 55.9, 54.7/54.2, 52.6,50.2/50.0, 48.5/48.1, 39.7, 26.6/26.5, 17.8.

Intermediate 36trans-(±)-3-Acetyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidine-1-carboxylicacid methyl ester

[0223] Prepared according to procedure set forth in U.S. Pat. No.5,665,754. Racemic form of Intermediate 46.

Intermediate 37trans-(±)-[3-Acetyl-4-(3-hydroxy-4-methoxyphenyl)-3-methyl]pyrrolidine-1-carboxylicacid methyl ester

[0224] A solution of Intermediate 34 (8.7 g, 21.9 mmol) in ethanol (50mL) was shaken for 16 hours under H₂ (50 psi) in the presence ofpalladium on carbon catalyst (0.5 g, 10% Pd/C). The catalyst wasfiltered off through a pad of diatomaceous earth followed by a 0.22 ummembrane filter. The filtrate was concentrated in vacuo to giveIntermediate 37 as a clear syrup (6.5 g, 97%).

[0225]¹H NMR (300 MHz, CDCl₃) δ: 6.79 (d, J=8.3 Hz, 1H), 6.74 (d, J=1.8Hz, 1H), 6.63 (br d, J=8.3 Hz, 1H), 6.04 (br s, 1H), 3.96-3.85 (m, 1H),3.87 (s, 3H), 3.75/3.73 (2 s, 3H), 3.74-3.59 (m, 3H), 3.36/3.26 (2 d,J=11.2/11.0 Hz, 1H), 2.17/2.15 (2 s, 3H), 1.01 (s, 3H). ¹³C NMR (75 MHz,CDCl₃) δ: 210.0/209.8, 155.3, 145.9/145.8, 145.5, 131.2/130.8, 119.9,114.5, 110.6, 58.1/57.2, 55.8, 54.4/53.9, 52.5, 50.3/50.1, 48.4/48.0,26.3, 17.6.

Intermediate 38trans-3-Acetyl-4-[exo-3-(bicyclo[2.2.1]hept-2-yl-oxy)-4-methoxyphenyl]-3-methylpyrrolidine-1-carboxylicacid methyl ester

[0226] Prepared by the Mitsunobu procedure of Intermediate 2 fromIntermediate 37 and endo-norborneol (36% yield).

[0227]¹H NMR (300 MHz, CDCl₃) δ: 6.80 (d, J=8.2 Hz, 1H), 6.66 (d, J=9.0Hz, 1H), 6.62 (s, 1H), 4.15-4.08 (m, 1H), 3.95-3.86 (m, 1H), 3.83 (s,3H), 3.74 (s, 3H), 3.73-3.60 (m, 3H), 3.37/3.28 (2 d, J=11.2/10.8 Hz,1H), 2.47 (br s, 1H), 2.32 (br s, 1H), 2.17/2.15 (2 s, 3H), 1.76-1.66(m, 2H), 1.63-1.45 (m, 3H), 1.28-1.08 (m, 3H), 1.02/1.01 (2 s, 3H). ¹³CNMR (75 MHz, CDCl₃) δ: 210.5/210.3, 155.7, 149.6, 147.4, 130.8/130.76,130.3, 120.9/120.7/120.5, 115.6/115.4/115.3/115.2, 112.2, 81.5,58.6/57.8, 56.4, 54.9/54.6, 52.9, 50.6/50.5, 49.1/49.0/48.7, 41.5, 40.4,35.8/35.7, 28.8, 26.9/26.8, 24.7/24.6, 18.2.

Intermediate 39trans-[3-Acetyl-4-[4-methoxy-3-(1-methyl-3-phenyl-propoxy)phenyl]-3-methylpyrrolidine-1-carboxylicacid methyl ester

[0228] Prepared by the Mitsunobu procedure of Intermediate 2 fromIntermediate 37 and 4-phenyl-2-butanol.

[0229]¹H NMR (300 MHz, CDCl₃) δ: 7.29-7.15 (m, 5H), 6.82 (d, J=8.3 Hz),6.72-6.63 (m, 2H), 4.33-4.25 (m, 1H), 3.94-3.59 (m, 4H), 3.84 (s, 3H),3.74 (br s, 3H), 3.36/3.27 (2 dd, J=11.2, 3.0/10.9, 3.9 Hz, 1H),2.88-2.69 (m, 2H), 2.18-2.06 (m, 4H), 1.95-1.82 (m, 1H), 1.33/1.31 (2 d,J=2.3/2.3 Hx, 3H), 1.01/0.99 (2 s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ:209.9, 155.4, 149.8, 147.1, 141.9, 130.4/129.9, 128.5, 128.4, 125.8,121.2, 116.9, 111.9, 74.8, 58.1/57.3, 55.9, 54.6/54.3, 52.6, 50.2/50.1,48.6/48.2, 38.1, 31.8, 26.6, 19.9, 17.7.

Intermediate 40trans-(±)-3-Acetyl-4-(4-methoxy-3-phenethyloxy-phenyl)-3-methylpyrrolidine-1-carboxylicacid methyl ester

[0230] Prepared by the Mitsunobu procedure of Intermediate 2 fromIntermediate 37 and 2-phenylethanol.

[0231]¹H NMR (300 MHz, CDCl₃) δ: 7.36-7.23 (m, 5H), 6.82 (d, J=8.2 Hz,1H), 6.70 (d, J=8.4 Hz, 1H), 6.66 (s, 1H), 4.18 (t, J=7.5 Hz, 2H),3.92-3.81 (m, 1H), 3.86 (s, 3H), 3.76-3.61 (m, 3H), 3.73 (s, 3H),3.40/3.27 (2 d, J=11.2/10.9 Hz, 1H), 3.15 (t, J=7.5 Hz, 2H) 2.16/2.12 (2s, 3H), 1.00 (s, 3H).

Intermediate 41trans-3-Acetyl-4-[4-methoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-3-methylpyrrolidine-1-carboxylicacid methyl ester

[0232] Prepared by the Mitsunobu procedure of Intermediate 2 fromIntermediate 37 and 3-hydroxytetrahydrofuran.

[0233]¹H NMR (300 MHz, CDCl₃) δ: 6.85-6.63 (m, 3H), 4.92-4.88 (m, 1H),4.07-3.62 (m, 8H), 3.84 (s, 3H), 3.75 (s, 3H), 3.39/3.29 (2 d,J=11.2/10.2 Hz, 1H), 2.19-2.14 (m, 5H), 1.02 (br s, 3H). ¹³C NMR (75MHz, CDCl₃) δ: 210.0/209.9, 155.4, 149.5, 146.5, 130.0, 121.6/121.5,116.5/116.4/116.3, 112.0, 111.0, 78.9, 73.0, 67.2, 58.1/57.3, 55.9,54.7/54.3, 52.6, 50.1/50.0, 48.4/48.0, 33.0, 26.6, 17.8.

Intermediate 42(4R)-3-{[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidin-3-yl]carbonyl}-4-phenyl-1,3-oxazolidin-2-one

[0234] To a cooled (−4° C.), stirred slurry of acyl oxazolidinone (9.30g, 22.8 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine(11.7 mL, 45.6 mmol, 2 eq.) in CHCl₃ (65 mL) was added a solution of TFAin CHCl₃ (4.6 mL of 1.0 M, 4.6 mmol, 0.2 eq.) via syringe under anitrogen atmosphere. The resulting slurry was stirred at about 0° C. for4 hours, then at about 15° C. overnight (water bath). The resultingcloudy solution then was recooled to −4° C., treated with an additionalportion of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (5.9mL, 22.8 mmol, 1 eq.) via syringe, and allowed to stir for 5 hours moreduring which time the reaction became homogenous. TLC (5% Et₂O inCH₂Cl₂) showed the reaction was complete. The bulk of the CHCl₃ wasremoved at reduced pressure, and the residue was diluted with EtOAc (250mL) and washed successively with 1 N aqueous HCl (2×50 mL), 1 N aqueousNaOH (50 mL) and brine (50 mL). The organic layer then was dried(MgSO₄), filtered and concentrated in vacuo to give an orange semi-solid(13.9 g). Purification via flash chromatography on silica gel (2% etherin CH₂Cl₂) provided the major diastereomer as a white foam (8.25 g,65%).

[0235] Diastereomeric selectivity about 10:1 (HPLC).

[0236]¹H NMR (400 MHz, CDCl₃) δ: 7.42-7.21 (c, 10H), 6.95 (s, 1H), 6.81(s, 2H), 5.55 (dd, 1H), 4.74 (t, 1H), 4.68 (m, 1H), 4.10 (dd, 1H), 3.93(t, 1H), 3.70 (d, 1H), 3.68 (s, 3H), 3.56 (d, 1H), 3.42 (d, 1H), 2.72(m, 2H), 2.64 (d, 1H), 2.48 (m, 1H), 1.85-1.78 (c, 2H), 1.75-1.61 (c,4H), 1.57-1.53 (c, 2H), 0.96 (s, 3H). LRMS (Electrospray, positive):Da/e 555.2 (m+1).

Intermediate 43(3S,4S)-1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidine-3-carboxylicacid

[0237] A suspension of lithium peroxide (0.5 g, 10.8 mmol) in water-THF(1:1, 6 mL) was added to a solution of Intermediate 42 (3.0 g, 5.4 mmol)in water-THF (3:1, 30 mL) at 0° C. under a nitrogen blanket. Thesuspension solubilized immediately. After 1 hour of stirring at 0° C.,an aqueous sodium sulfite (Na₂SO₃) solution (1.5 N, 12 mL) was added toquench excess peroxide, and THF was removed under reduced pressure. Thebasic residue was extracted with three 30 mL portions of CH₂Cl₂. Theaqueous phase was acidified to pH 1 with aqueous 1.0 N HCl solution, andextracted with three 30 mL portions of Et₂O. The ether extracts weredried (Na₂SO₄), concentrated under reduced pressure and used withoutfurther purification.

[0238]¹H NMR (300 MHz, CDCl₃) δ: 10.73 (br. s, 1H, COOH), 7.69 (br. s,2H, aromatic), 7.38-7.36 (m, 3H, aromatic), 6.78 (s, 1H, aromatic), 6.69(m, 2H, aromatic), 4.71 (br. s, 1H), 4.51-4.48 (m, 2H), 4.24-4.11 (br.s, 2H), 4.08-3.88 (br. s, 1H), 3.76 (s, 3H, OCH₃), 3.54 (br. s, 1H), 3.1(br. s, 1H), 1.83-1.52 (m, 8H, cyclopentyl), 1.05 (br. s, 3H, CH₃).

Intermediate 44(3S,4S)-1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidine-3-carboxylicacid methoxy methyl amide

[0239] Intermediate 44 was prepared from Intermediate 43 (2.1 g, 4.98mmol), 1,1′-carbonyldiimidazole (0.89 g, 5.47 mmol), andN,O-dimethylhydroxylamine hydrochloride (0.73 g, 7.47 mmol) to provideIntermediate 44 (0.9 g, 40%) as a white crystalline powder.

[0240]¹H NMR (300 MHz, CDCl₃) δ: 7.4-7.3 (m, 5H, aromatic), 7.06 (d, 1H,J=1.7 Hz, aromatic), 6.89 (dd, 1H, J=8.3 Hz, aromatic), 6.73 (d, 1H,J=8.3 Hz, aromatic), 4.77-4.75(m, 1H), 4.16-4.06(m, 1H), 3.81 (s, 3H,OCH₃), 3.81-3.71 (m, 2H), 3.60 (s, 3H, OCH₃) 3.21 (s, 3H, NCH₃), 2.96(d, 1H, J=9.6 Hz,), 2.91 (m, 1H), 2.78 (d, 1H, J=9.6 Hz,), 2.77 (m, 1H),2.04 (s, 3H, CH₃), 1.92-1.59 (m, 8H, cyclopentyl), 0.94 (s, 3H, CH₃).

Intermediate 451-[(3S,4S)-1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethanone

[0241] A solution of Intermediate 44 (0.17 g, 0.43 mmol) in THF (8 mL)was cooled to −78° C. and treated with methyllithium (1.5 M in THF,0.315 mL, 0.47 mmol) under a nitrogen blanket. The solution was stirredfor 40 minutes at −78° C., then quenched with a cold saturated aqueousNH₄Cl solution (8 mL). A mixture of hexanes/CH₂Cl₂ (3:1, 8 mL) was addedwith vigorous stirring. After a further dilution with morehexanes/CH₂Cl₂ (3:1, 10 mL), brine (10 mL) was added and the two layersseparated. The aqueous layer was washed with CH₂Cl₂ (8 mL) and thecombined organic extracts washed with brine, dried (Na₂SO₄), filtered,and concentrated under reduced pressure into an oil product (154 mg,89%).

[0242]¹H NMR (300 MHz, CDCl₃) δ: 7.39-7.24 (m, 5H, aromatic), 6.82-6.70(m, 3H, aromatic), 4.74 (br. s, 1H), 3.81 (s, 3H, OCH₃), 3.78-3.58 (m,3H), 3.14 (d, 1H, J=9.7 Hz ), 3.05 (m, 1H), 2.84 (m, 1H), 2.40 (d, 1H,J=9.7 Hz,), 2.23 (s, 3H, CH₃), 1.92-1.59 (m, 8H, cyclopentyl), 0.83 (s,3H, CH₃).

Intermediate 46(3S,4S)-3-Acetyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidine-1-carboxylicacid methyl ester

[0243] To a stirred solution of Intermediate 45 (0.154 g, 0.38 mmol) inanhydrous acetonitrile (10 mL) was added methyl chloroformate (0.146 mL,1.89 mmol). The solution was heated to 80° C. and refluxed for 3 hours.The solution then was cooled to room temperature, and concentrated underreduced pressure. Purification by reversed-phase HPLC providedIntermediate 46 as an oil (93 mg, 65%). Specific rotation: [α]₂₅₉²³=+2.5 (c=1.0, EtOH).

[0244]¹H NMR (300 MHz, CDCl₃) δ: 6.8 (d, 1H, J=8.0 Hz, aromatic), 6.66.(d, 1H, J=8.0 Hz, aromatic), 6.66 (s, 1H, aromatic), 4.73(s, 1H),3.95-3.64(m, 4H), 3.83 (s, 3H, OCH₃), 3.74 (s, 3H, OCH₃), 3.37 and3.27(s, 3H, CH₃), 2.17 and 2.14 (s, 3H, CH₃), 1.92-1.59 (m, 8H,cyclopentyl), 1.03 and 1.02 (s, 3H, CH₃).

Intermediate 47(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidine-3-carbaldehyde

[0245] General Oxazolidinone Reduction/Oxidation Procedure

[0246] To a cooled (−78° C.), stirred solution of Intermediate 42 (15.09g, 27.2 mmol) in toluene (250 mL) was added a solution of lithiumaluminum hydride in tetrahydrofuran (16.3 mL of 1.0 M, 16.3 mmol, 0.6eq.) via syringe under a nitrogen atmosphere. Vigorous bubbling wasobserved. The resulting solution was allowed to stir at −78° C. for 2hours, after which time the cooling bath was removed. The reaction wasquenched with the successive addition of water (0.62 mL), 15% aqueousNaOH (0.62 mL), and water (1.9 mL). The resulting mixture was allowed towarm to room temperature, stirred for 30 minutes, then diluted with Et₂O(500 mL) and dried (MgSO₄) Filtration and concentration in vacuoprovided the alcohol (with some aldehyde present) as a semi-solid (14.8g). This material was used immediately without further purification.

[0247] To a cooled (−78° C.), stirred solution of oxalyl chloride inCH₂Cl₂ (10.9 mL of 2.0 M, 21.8 mmol, 0.8 eq.) in more CH₂Cl₂ (75 mL) wasadded DMSO (3.1 mL, 43.5 mmol, 1.6 eq.) via syringe under nitrogenatmosphere. After stirring at −78° C. for 20 minutes, a solution of thecrude alcohol in CH₂Cl₂ (75 mL) was added by cannula. The resultingyellow solution was allowed to stir at −78° C. for 20 minutes, then Et₃N(15.2 mL, 109 mmol, 4 eq.) was added by syringe. The reaction wasallowed to stir at −78° C. for 20 minutes, then warmed to roomtemperature and stirred for an additional 1 hour. The reaction wasquenched with the addition of brine (150 mL), then extracted with CH₂Cl₂(2×100 mL). Combined organic layers were dried (MgSO₄), filtered andconcentrated in vacuo to provide the crude aldehyde. Purification byflash silica gel chromatography (25% EtOAc in hexanes) provided thealdehyde as a clear, colorless oil (9.8 g, 92%).

[0248]¹H NMR (400 MHz, CDCl₃) δ: 9.64 (s, 1H), 7.37-7.26 (c, 5H),6.78-6.76 (c, 2H), 6.70 (m, 1H), 4.74 (m, 1H), 3.82 (s, 3H), 3.70 (m,1H), 3.64-3.62 (c, 2H), 3.18-3.13 (c, 2H), 2.84 (t, 1H), 2.41 (d, 1H),1.94-1.83 (c, 6H), 1.63-1.59 (c, 2H), 0.74 (s, 3H) LRMS (Electrospray,positive): Da/e 394.3 (m+1).

Intermediate 48(4R)-3-{[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidin-3-yl]carbonyl}-4-phenyl-1,3-oxazolidin-2-one

[0249] Prepared via the azomethine cycloaddition procedure ofIntermediate 23 from Intermediate 17.

[0250]¹H NMR (400 MHz, CDCl₃) δ: 7.45-7.12 (m, 15H), 6.95 (d, 1H), 6.78(d, 1H), 5.54 (dd, 1H), 5.17 (c, 1H), 4.69 (t, 1H), 4.22 (dd, 1H), 4.11(t, 1H), 3.84-3.60 (m, 5H), 3.51 (d, 1H), 3.37 (dt, 2H), 3.21 (dd, 2H),2.90 (d, 1H), 2.85 (dd, 1H), 2.76 (dd, 1H), 1.12 (s, 3H).

Intermediate 49(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidine-3-carbaldehyde

[0251] Prepared from Intermediate 48 via the reduction/oxidationprocedure of Intermediate 47.

[0252]¹H NMR (400 MHz, CDCl₃) δ: 9.65 (s, 1H), 7.36-7.17 (m, 9H), 6.84(d, 1H), 6.79 (d, 1H), 6.76 (dd, 1H), 5.16 (c, 1H), 3.79 (s, 3H), 3.76(d, 1H), 3.68-3.63 (c, 1H), 3.40-3.31 (m, 2H), 3.24-3.13 (m, 2H), 2.85(dd, 1H), 2.43 (d, 1H) 0.77 (s, 3H).

Intermediate 50(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidin-3-yl]ethan-1-ol

[0253] Desired, more polar diastereomer. Prepared via the Grignardaddition procedure of Intermediate 56 from Intermediate 49.

[0254]¹H NMR (400 MHz, CDCl₃) δ: 7.39-7.17 (m, 9H), 6.84-6.77 (m, 3H),5.17 (c, 1H), 3.80 (s, 3H), 3.72-3.57 (m, 4H), 3.38-3.19 (m, 5H), 3.11(d, 1H), 2.57 (t, 1H), 2.12 (d, 1H), 1.15 (d, 3H), 0.51 (s, 3H).

Intermediate 51(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethan-1-ol

[0255] Prepared via the debenzylation procedure of Intermediate 31 fromIntermediate 50.

[0256]¹H NMR (400 MHz, CDCl₃) δ: 7.26-7.16 (m, 4H), 6.81 (s, 3H), 5.19(c, 1H), 3.80 (s, 3H), 3.74-3.68 (m, 2H), 3.44-3.17 (m, 8H), 2.66 (d,1H), 2.51 (br s, 1H), 1.18 (d, 3H), 0.63 (s, 3H).

Intermediate 52(4R)-3-({(3S,4S)-4-[4-Methoxy-3-(phenylmethoxy)-phenyl]-3-methyl-1-benzylpyrrolidin-3-yl}carbonyl)-4-phenyl-1,3-oxazolidin-2-one(Major Diastereomer)

[0257] Prepared via the cycloaddition procedure of Intermediate 23 fromIntermediate 21.

[0258]¹H NMR (400 MHz, CDCl₃) δ: 7.49-7.23 (m, 15H), 7.09 (d, 1H), 6.94(dd, 1H), 6.80 (d, 1H), 5.49 (dd, 1H), 5.17 (s, 2H), 4.66 (t, 1H), 4.19(dd, 1H), 4.09 (t, 1H), 3.87 (s, 3H), 3.68 (q, 2H), 3.51 (d, 1H),2.85-2.79 (m, 2H), 2.69 (dd, 1H), 0.99 (s, 3H).

Intermediate 53(3S,4S)-4-(4-Methoxy-3-(phenylmethoxy)phenyl)-3-methyl-1-benzylpyrrolidine-3-carbaldehyde

[0259] Prepared via the reduction/oxidation procedure of Intermediate 47from Intermediate 52.

[0260]¹H NMR (400 MHz, CDCl₃) δ: 9.56 (s, 1H), 7.43-7.22 (m, 10H), 6.79(d, 1H), 6.77 (d, 1H), 6.71 (dd, 1H), 5.14 (dd, 2H), 3.86 (s, 3H), 3.71(d, 1H), 3.62 (d, 1H), 3.57 (d, 1H), 3.13-3.08 (m, 2H), 2.73 (dd, 1H)2.30 (d, 1H), 0.58 (s, 3H) LRMS (Electrospray, positive): m/z 416.3(m+1).

Intermediate 543-[1-Benzyl-4-S-(3-tert-butoxy-4-methoxyphenyl)-3-S-methylpyrrolidine-3-carbonyl]-4-R-phenyl-oxazolidin-2-one

[0261] To a stirred solution of Intermediate 22 (39.8 gm, 97 mmol) inCHCl₃ (292 mL) at 0° C. under a nitrogen blanket was addedN-(methoxymethyl)-N-(trimethyl-silylmethyl)benzylamine (49.5 mL, 194mmol) followed by TFA acid (1M in CHCl₃, 9.7 mL, 9.7 mmol). The slurrywas allowed to warm to room temperature overnight. TLC in 2/3EtOAc/hexane indicated partial conversion of starting material to aslightly higher R_(f) product. The resultant solution was treated withmore N-(methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (25 mL, 97mmol) to consume residual starting material. After 3 hours at roomtemperature, the reaction appeared complete by TLC. The solution wasconcentrated by rotory evaporator, then redissolved in EtOAc (500 mL).The organics were washed with 2N HCl (2×500 mL), 1N NaOH (2×500 mL), andsaturated NaCl (1×500 mL). The organics were dried (MgSO₄), filtered,and concentrated in vacuo to give Intermediate 54 as an approximately12:1 ratio of diastereomers. Chromatography on a 110 mm×8″ column with1/3 EtOAc/hexane provided, after concentration in vacuo of pooledfractions, Intermediate 54 (40 gm, 76%) as a yellow foam.

[0262]¹H-NMR (CDCl₃, 400 MHz) δ: 7.42-7.20 (m, 10H), 7.11 (s, 1H), 7.05(d, 1H), 6.76 (d, 1H), 5.53 (dd, 1H), 4.65 (dd, 1H), 4.20 (dd, 1H), 4.08(dd, 1H), 3.77 (s, 3H), 3.65 (dd, 2H), 3.51 (d, 1H), 2.82 (dd, 1H), 2.81(d, 1H), 2.71 (dd, 1H), 1.34 (s, 9H), 1.06 (s, 3H).

Intermediate 55(3R)-4-[3-(tert-Butoxy)-4-methoxyphenyl]-3-methyl-1-benzylpyrrolidine-3-carbaldehyde

[0263] To a stirred solution of Intermediate 54 (21.5 gm, 39.7 mmol) intoluene (400 mL) at −78° C. under a nitrogen blanket was added lithiumaluminum hydride (1M in THF, 24 mL, 24 mmol) dropwise by syringe over 10minutes. After 15 minutes, TLC in 4/1 CH₂Cl₂/Et₂O showed completeconsumption of starting material and appearance of a lower R_(f)material. Methanol (4 mL) in toluene (40 mL) was added carefully bysyringe at −78° C. with gas evolution. When gas evolution ceased, thereaction was allowed to warm to room temperature, then treated withwater (1 mL), 3N NaOH (2 mL), and water (1 mL) sequentially. After 10minutes, the reaction was diluted with Et₂O (300 mL) and stirred for 15minutes. Magnesium sulfate was added and the mixture filtered throughGF/F. filter paper with Et₂O. The crude product was concentrated invacuo and appeared by ¹H-NMR to be an approximately 4:1 mixture ofdesired aldehyde over reduced alcohol. The crude product was dissolvedin CH₂Cl₂ (40 mL). Separately, oxalyl chloride (2M in CH₂Cl₂, 11.2 mL,22.4 mmol) was stirred at −60° C. under a nitrogen blanket and treatedwith DMSO (3.1 mL, 44 mmol) in CH₂Cl₂ (15 mL) dropwise by syringe. After5 minutes, the aldehyde/alcohol mixture solution was added to the oxalylchloride/DMSO solution by cannula. The reaction was stirred at −60° C.for 45 minutes, then treated with Et₃N (13.8 mL, 100 mmol) and allowedto warm to room temperature. The solution was diluted to 200 mL withCH₂Cl₂ and washed with water (1×200 mL), 2N HCl (2×200 mL), saturatedNaHCO₃ (2×200 mL), and saturated NaCl (1×200 mL). The organic layerswere dried (MgSO₄), filtered, and concentrated in vacuo to a yellow oilwhich was dissolved in 3/1 hexane/EtOAc. After dissolution, the cleavedphenyl oxazolidinone precipitated and was removed by filtration. Thefiltrate was chromatographed on a 70 mm×8″ column with 3/1 hexane/EtOActo provide (after concentration of product containing fractions invacuo) pure Intermediate 55 as a yellow oil (13.7 gm, 90%)

[0264]¹H-NMR (400 MHz, CDCl₃) δ: 9.62 (s, 1H), 7.37-7.22 (m, 5H), 6.92(s, 1H), 6.84 (d, 1H), 6.79 (d, 1H), 3.79 (s, 3H), 3.71 (dd, 2H), 3.62(dd, 1H), 3.17 (dd, 1H), 2.80 (dd, 1H), 2.38 (d, 1H), 1.35 (s, 9H), 0.73(s, 3H).

Intermediate 56(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidin-3-yl]ethan-1-ol

[0265] Grignard Addition Procedure

[0266] To a cooled (0° C.), stirred solution of Intermediate 47 (0.96mg, 2.45 mmol) in dry Et₂O (10 mL) was added a solution ofmethylmagnesium iodide (or other Grignard reagent) in ether (2.45 mL of3.0 M, 7.35 mmol, 3 eq.) via syringe under a nitrogen atmosphere. Afterstirring at 0° C. for 15 minutes, the reaction was allowed to warm toroom temperature and stirred for 2 hours. The reaction then wascarefully quenched with saturated aqueous NH₄Cl (40 mL), and extractedwith EtOAc (3×50 mL). Combined organic layers were washed with brine,dried (Na₂SO₄) filtered, and concentrated in vacuo to give 990 mg of anorange oil. Purification via flash silica gel chromatography (CH₂Cl₂ to5% methanol in CH₂Cl₂) afforded the less polar diastereomer (419 mg,42%) and the more polar diastereomer (375 mg, 37%) as colorless, viscousoils.

[0267] Less Polar Diastereomer:

(1S)-1-[(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidin-3-yl]ethan-1-ol

[0268]¹H NMR (400 MHz, CDCl₃) δ: 7.34-7.28 (c, 5H), 6.79-6.73 (c, 3H),4.74 (m, 1H), 3.82 (s, 3H), 3.74 (q, 1H), 3.65 (q, 2H), 3.53 (t, 1H),3.40 (t, 1H), 2.99 (d, 1H), 2.50 (t, 1H), 2.35 (d, 1H), 1.94-1.81 (c,6H), 1.63-1.59 (c, 2H), 1.10 (d, 3H), 0.52 (s, 3H). LRMS (Electrospray,positive): Da/e 410.3 (m+1).

[0269] More Polar Diastereomer:

(1R)-1-[(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidin-3-yl]ethan-1-ol

[0270]¹H NMR (400 MHz, CDCl₃) δ: 7.33-7.31 (c, 5H), 6.79-6.72 (c, 3H),4.74 (m, 1H), 3.82 (s, 3H), 3.69-3.56 (c, 4H), 3.29 (t, 1H), 3.10 (d,1H), 2.56 (t, 1H), 2.09 (d, 1H), 2.04 (s, 3H), 1.92-1.81 (c, 6H),1.62-1.59 (c, 2H), 1.13 (d, 3H), 0.47 (s, 3H). LRMS (Electrospray,positive): Da/e 410.3 (m+1).

Intermediate 57(1S)-1-{(3S,4S)-4-[4-Methoxy-3-(phenylmethoxy)-phenyl]-3-methyl-1-benzylpyrrolidin-3-yl}ethan-1-ol

[0271] Less polar diastereomer. Prepared via the Grignard procedure ofIntermediate 56 from Intermediate 53.

[0272]¹H NMR (400 MHz, CDCl₃) δ: 7.44-7.22 (m, 10H), 6.80 (d, 1H), 6.75(dd, 1H), 6.67 (d, 1H), 5.17 (s, 2H), 3.88 (s, 3H), 3.66 (q, 1H), 3.60(d, 2H), 3.43 (t, 1H), 2.92 (d, 1H), 2.38 (t, 1H), 2.22 (d, 1H), 0.98(d, 3H), 0.32 (s, 3H) LRMS (Electrospray, positive): m/z 432.5 (m+1).

Intermediate 58(1R)-1-{(3S,4S)-4-[4-Methoxy-3-(phenylmethoxy)-phenyl]-3-methyl-1-benzylpyrrolidin-3-yl}ethan-1-ol

[0273] More polar, desired diastereomer. Prepared via the Grignardprocedure of Intermediate 56 from Intermediate 53.

[0274]¹H NMR (400 MHz, CDCl₃) δ: 7.43-7.21 (m, 10H), 6.79 (d, 1H),6.75-6.70 (m, 2H), 5.16 (dd, 2H), 3.87 (s, 3H), 3.64-3.49 (m, 4H), 3.23(t, 1H), 3.06 (d, 1H), 2.46 (t, 1H), 1.99 (d, 1H), 1.07 (d, 3H), 0.28(s, 3H). LRMS (Electrospray, positive): m/z 432.5 (m+1).

Intermediate 59

[0275]1-R-[1-Benzyl-4-S-(3-tert-butoxy-4-methoxyphenyl)-3-S-methylpyrrolidin-3-yl]ethanol

[0276] To a stirred solution of trimethylaluminum (2M in toluene, 59.4mL, 119 mmol) at 0° C. under a nitrogen blanket was addedmethylmagnesium iodide (3M in Et₂O, 36 mL, 108 mmol). After 30 minutesat 0° C., the organometallic solution was added via cannulation to asolution of Intermediate 55 (13.7 gm, 36 mmol) in CH₂Cl₂ (360 mL) at−78° C. under a nitrogen blanket. After complete addition, the reactionwas stirred at −78° C. for 6 hours. The reaction then was warmed to 0°C. and carefully poured into ice cold 1M potassium sodium tartrate (1500mL) with rapid stirring, and diluted with EtOAc (1500 mL). Afterstirring for 15 minutes, the layers were separated and the organicswashed with 1M potassium sodium tartrate (1×1000 mL) and saturated NaCl(1×1000 mL). The organics were dried (MgSO₄), filtered, and concentratedin vacuo to provide a 2.5:1 mixture of diastereomers plus approximately10% residual starting aldehyde by crude ¹H-NMR. The crude product waschromatographed on a 110 mm×8″ column with 3/7/0.4 EtOAc/hexane/MeOH toprovide, after pooling and concentration in vacuo of the desired lowerR_(f) diastereomer containing fractions, Intermediate 59 (8.1 gm, 57%)as an orange oil.

[0277]¹H-NMR (CDCl₃, 400 MHz) δ: 7.34-7.23 (m, 5H), 6.86 (m, 3H), 6.79(d, 1H), 3.79 (s, 3H), 3.65 (dd, 1H), 3.62 (s, 2H), 3.58 (dd, 1H), 3.29(dd, 1H), 3.10 (d, 1H), 2.53 (dd, 1H), 2.07 (d, 1H), 1.35 (s, 9H), 1.12(d, 3H), 0.45 (s, 3H).

Intermediate 603-(3-Cyclopropylmethoxy-4-methoxyphenyl)-2-methyl-E-acrylic acid ethylester

[0278] A round-bottomed flash was charged with THF (850 mL) and triethyl2-phosphonopropionate (97.2 g, 0.408 mol) and the resulting mixture wascooled to 0° C. Lithium hexamethyldisilazide (1.0 M in THF, 489 mL,0.489 mol) then was added dropwise. The mixture was stirred for 30minutes at 0° C., then a solution of Intermediate 1 (70 g, 0.34 mol) inTHF (100 mL) was added. After the dropwise addition, the reactionmixture was maintained at 22° C. for 62 hours. The reaction was quenchedwith saturated NaCl and diluted with EtOAc. After separation, theorganic layer was washed with saturated NaCl, dried over Na₂SO₄, andconcentrated in vacuo. The green oil was purified by chromatographythrough a pad of SiO2 (650 g) using EtOAc/hexanes (1:10) as eluant,(40.8 g).

[0279]¹H NMR (400 MHz, CDCl₃) δ: 7.67-7.61 (m, 1H), 7.07-7.02 (m, 1H),6.98-6.95 (m, 1H), 6.92-6.89 (m, 1H), 4.32-4.25 (m, 2H), 3.92 (s, 3H),3.90-3.85 (m, 2H), 2.15 (s, 3H), 1.38-1.32 (m, 4H), 0.70-0.63 (m, 2H),0.41-0.37 (m, 2H).

Intermediate 613-(3-Cyclopropylmethoxy-4-methoxyphenyl)-2-methyl-E-acrylic acid

[0280] Intermediate 60 (26.9 g, 93 mmol) was dissolved in 1,4-dioxane(95 mL) and treated with a solution of LiOH monohydrate (4.6 g, 111mmol) dissolved in water (95 mL). The resulting solution was heated at80° C. for 3 hours, then stirred overnight at room temperature. Thereaction mixture was poured into water (350 mL) and extracted twice withEt₂O (500 mL total). The aqueous layer was diluted with EtOAc (350 mL)and the pH was adjusted with concentrated H₃PO₄ (24 mL) The layers wereseparated, the EtOAc layer was washed with water and saturated NaCl,dried over MgSO₄, and concentrated in vacuo (20.4 9).

[0281]¹H NMR (400 MHz, CDCl₃) δ: 7.77 (s, 1H), 7.11-7.07 (dd, 1H),7.02-6.98 (d, 1H), 6.93-6.90 (d, 1H), 3.93 (s, 3H), 3.86 (d, 2H), 2.18(s, 3H), 1.39-1.31 (m, 1H), 0.69-0.63 (m, 2H), 0.39-0.35 (m, 2H).

Intermediate 623-(3-Cyclopropylmethoxy-4-methoxyphenyl)-2-methyl-E-acryloyl chloride

[0282] Intermediate 61 (55.8 g, 0.213 mol) was dissolved in CH₂Cl₂ (300mL) and cooled to 0° C. with a drying tube attached. Oxalyl chloride(2.0 M in CH₂Cl₂, 117 mL, 0.234 mol) was added followed by addition ofDMF (1.0 mL). The reaction mixture was maintained at 22° C. for severalhours. The mixture was diluted with CH₂Cl₂ and washed with water,saturated NaCl, then dried over Na₂SO₄, and concentrated in vacuo (65.1g yellow solid).

[0283]¹H NMR (400 MHz, CDCl₃) δ: 7.97 (s, 1H), 7.16-7.11 (dd, 1H),7.03-7.00 (d, 1H), 6.95-6.91 (dd, 1H), 3.93 (s, 3H), 3.87 (d, 2H), 2.23(s, 3H), 1.39-1.31 (m, 1H), 0.69-0.64 (m, 2H), 0.40-0.37 (m, 2H).

Intermediate 633-[3-(3-Cyclopropylmethoxy-4-methoxyphenyl)-2-methyl-E-acryloyl]-4-(R)-phenyloxazolidin-2-one

[0284] 4-(R)-Phenyloxazolidin-2-one (33.0 g, 0.202 mol) was dissolved inTHF (1 L) and cooled to −78° C. n-Butyl lithium (2.5 M in hexanes, 79.5mL, 0.198 mol) was added, and the resulting reaction mixture was stirredfor 20 minutes. A solution of Intermediate 62 (65.1 g, 0.213 mol) in THF(200 mL) was added dropwise over 15 minutes. The reaction mixture wasstirred for 1 hour at −78° C., then warmed to 0° C., slowly. Thereaction mixture became thick with beige solids. The mixture wasneutralized at 0° C. with saturated NH₄Cl (600 mL) and water (300 mL)The solution was warmed to 22° C. quickly and poured into CHCl₃ (2400mL). After shaking and separation, the organic layer was washed withwater (1 L), saturated NaCl (1 L), dried over Na₂SO₄, and concentratedin vacuo to a pale orange solid (94.4 g).

[0285]¹H NMR (400 MHz, CDCl₃) δ: 7.41-7.32 (m, 5H), 7.07-6.98 (m, 2H),6.95-6.93 (d, 1H), 6.90-6.86 (d, 1H), 5.55-5.51 (dd, 1H), 4.77-4.71 (dd,1H), 4.30-4.26 (dd, 1H), 3.91 (s, 3H), 3.85 (d, 2H), 2.17 (s. 3H),1.38-1.29 (m, 1H), 0.66-0.62 (m, 2H), 0.39-0.34 (m, 2H).

Intermediate 643-[1-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidine-3-carbonyl]-4-(R)-phenyloxazolidin-2-one

[0286] Intermediate 63 (94.4 g, 0.21 mol) was dissolved in CHCl₃ (640mL), then cooled to 0° C. Benzylmethoxy-methyltrimethylsilanylmethylamine (95 g, 0.40 mol) was added,and the reaction mixture was treated dropwise with a solution of TFA(3.08 mL) in CHCl₃ (40 mL). The reaction was stirred overnight whilewarming to 22° C. Additional benzylmethoxymethyl-trimethylsilanylmethylamine (71.2 g, 0.3 mol) was added,then the mixture was stirred for an additional 68 hours. The reactionwas quenched with saturated NH₄Cl (600 mL) and separated. The organiclayer was washed twice with 1 N HCl (500 mL), once with water, once with1 N NaOH (500 mL), once with water, once with 6% NaHCO3, once withsaturated NaCl, dried over Na₂SO₄, and concentrated in vacuo. The crudematerial was chromatographed on SiO₂ (1.2 kg) in two portions usinghexanes/EtOAc (2:1) as eluant (62.3 g).

[0287]¹H NMR (400 MHz, CDCl₃) δ: 7.44-7.20 (m, 10H), 7.07 (d, 1H),6.94-6.91 (dd, 1H), 6.78-6.76 (d, 1H), 5.56-5.50 (dd, 1H), 4.69-4.63(dd, 1H), 4.21-4.16 (dd, 1H), 3.83-3.80 (m, 2H), 3.82 (s, 3H), 3.74-3.70(d, 1H), 3.64-3.59 (d, 1H), 3.50-3.46 (d, 1H), 2.90-2.86 (d, 1H),2.83-2.71 (m, 2H), 1.36-1.29 (m, 1H), 0.64-0.60 (m, 2H), 0.38-0.32 (m,2H).

Intermediate 651-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidine-3-carbaldehyde

[0288] Intermediate 64 (62.3 g, 0.115 mol) was dissolved in toluene (1L), then cooled to −78° C. The solution was treated with lithiumaluminum hydride (1.0 M in THF, 69 mL, 69 mmol) by slow addition. Thereaction was stirred for 0.5 hours, then quenched at −78° C. with adropwise addition of MeOH (13 mL). The reaction was stirred for 5minutes at −78° C., warmed to 0° C., followed by an addition of water(2.62 mL), 15% NaOH (2.62.mL), and water (7.85 mL). The solution wasstirred for 10 minutes, then Et₂O was added (1.5 L) and the resultingmixture was stirred overnight at 22° C. Magnesium sulfate was added andafter stirring for 15 minutes, the solution was filtered through MgSO₄and concentrated in vacuo. NMR showed that the products of this reactionwere a mixture of the desired aldehyde and the primary alcohol (about4:1). This material was used without further purification in thefollowing Swern oxidation below. Oxalyl chloride (2.0 M in CH₂Cl₂, 25mL, 50 mmol) was added to CH₂Cl₂ (75 mL) and cooled to −60° C.Dimethylsulfoxide (7.1 mL, 100 mmol) was added as a solution in CH₂Cl₂(30 mL) in a dropwise manner. After 5 minutes, a solution ofaldehyde/alcohol mixture (4:1, ˜0.115 mol, (ca. 0.05 mol alcohol))dissolved in CH₂Cl₂ was added dropwise. The mixture was stirred for 30minutes, then Et₃N (31 mL, 222 mmol) was added, and the solution waswarmed to 22° C. and stirred overnight. The reaction was quenched withwater and stirred vigorously for 20 minutes, then separated. The aqueouslayer was washed with CH₂Cl₂. The combined organic layers were washedwith saturated NaCl, dried over Na₂SO₄, and concentrated in vacuo.Intermediate 65 was purified by filter chromatography usinghexanes/EtOAc (4:1) as eluant (42 g).

[0289]¹H NMR (400 MHz, CDCl₃) δ: 9.64 (s, 1H), 7.39-7.23 (m, 5H),6.81-6.71 (m, 3H), 3.83 (s, 3H), 3.83-3.81 (m, 2H), 3.80-3.75 (d, 1H),3.67-3.61 (m, 2H), 3.19-3.11 (m, 2H), 2.86-2.81 (m, 1H), 2.43-2.40 (m,1H), 1.38-1.29 (m, 1H), 0.76 (s, 3H), 0.68-0.62 (m, 2H), 0.30-0.37 (m,2H).

Intermediate 661-[1-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]ethanol

[0290] Trimethylaluminum (2.0 M in toluene, 2.1 mL, 4.2 mmol) was cooledto 0° C. and methylmagnesium iodide (3.0 M in ethyl ether, 1.3 mL, 3.95mmol) was added dropwise. This grey suspension was stirred at 0° C. for30 minutes then it was added through a cannula to a solution ofIntermediate 65 (0.5 g, 1.3 mmol) dissolved in CH₂Cl₂ (6.6 mL), whichwas cooled to −78° C. The reaction mixture was stirred at −78° C. for 6hours. The mixture then was poured directly into a separatory funnelcontaining Rochelle's salt (1 M, 150 mL). The residue was rinsed intothe funnel with EtOAc. The mixture was diluted with EtOAc and separated.The organic layer was washed a second time with Rochell's salt, followedby saturated NaCl, dried over MgSO₄, and concentrated in vacuo. Thecrude product was a mixture (1:1) of the two diasteromeric alcohols plusa small amount of aldehyde. These materials were separable bychromatography on SiO₄ with EtOAc/hexanes (1:1).

[0291] Desired more polar carbinol:

[0292]¹H NMR (400 MHz, CDCl₃) δ: 7.36-7.30 (m, 3H), 7.28-7.24 (m, 2H),6.81-6.74 (m, 3H), 3.85 (s, 3H), 3.84-3.79 (m, 2H), 3.71-3.56 (m, 4H),3.33-3.25 (dd, 1H), 3.12-3.09 (d, 1H), 2.59-2.53 (dd, 1H), 2.16-2.08 (d,1H), 1.38-1.25 (m, 1H), 1.16 (d, 3H), 0.69-0.61 (m, 2H), 0.49 (s, 3H),0.39-0.35 (m, 2H).

Intermediate 67(1R)-1-{(3S,4S)-4-[3-(Cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidin-3-y1}ethan-1-ol

[0293] Prepared from Intermediate 66 by the debenzylation procedure ofIntermediate 31.

[0294]¹H NMR (400 MHz, CDCl₃) δ: 6.88-6.71 (m, 3H), 3.92-3.56 (c, 11H),3.14-3.05 (m, 1H), 1.37-1.25 (m, 1H), 1.20 (d, 2H), 0.72 (s, 3H), 0.63(d, 2H), 0.37 (d, 2H). LRMS (Electrospray, positive): Da/e 306.2 (m+1).

Intermediate 68(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethan-1-ol

[0295] Prepared by the debenzylation procedure of Intermediate 31 fromthe 1-(R) carbinol isomer (more polar diastereomer) of Intermediate 56.

[0296]¹H NMR (400 MHz, CDCl₃) δ: 6.81 (d, 1H), 6.75-6.73 (m, 2H), 4.80(c, 1H), 3.82 (s, 3H), 3.79-3.68 (m, 5H), 3.61 (t, 1H), 3.10 (d, 1H),1.96-1.80 (m, 6H), 1.63-1.57 (m, 2H), 1.21 (d, 3H), 0.72 (s, 3H). LRMS(Electrospray, positive): Da/e 320.4 (m+1).

Intermediate 69(1S)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethan-1-ol

[0297] Prepared by the debenzylation procedure of Intermediate 31 fromthe 1-(S) isomer (less polar intermediate) of Intermediate 56. LRMS(Electrospray, positive): Da/e 320.4 (m+1).

Intermediate 705-[4-((1R)-1-Hydroxyethyl)(3S,4S)-4-methylpyrrolidin-3-yl]-2-methoxyphenol

[0298] Prepared from Intermediate 58 via the debenzylation procedure ofIntermediate 31 (10% palladium on carbon used in place of palladiumacetate).

[0299]¹H NMR (400 MHz, CDCl₃) δ: 6.72 (d, 1H), 6.67 (d, 1H), 6.59 (dd,1H), 3.80 (s, 3H), 3.60 (qd, 1H), 3.29-3.17 (m, 6H), 3.10 (t, 1H), 2.55(d, 1H), 1.06 (d, 3H), 0.56 (s, 3H). LRMS (Electrospray, positive): m/z252.1 (m+1).

Intermediate 711-R-[1-Benzyl-4-S-(3-tert-butoxy-4-methoxyphenyl)-3-S-methylpyrrolidin-3-yl]-ethanol

[0300] To a stirred solution of trimethylaluminum (2M in toluene, 59.4mL, 119 mmol) at 0° C. under a nitrogen blanket was addedmethylmagnesium iodide (3M in Et₂O, 36 mL, 108 mmol). After 30 minutesat 0° C., the organometallic solution was added via cannula to asolution of Intermediate 55 (13.7 gm, 36 mmol) in CH₂Cl₂ (360 mL) at−78° C. under a nitrogen blanket. After complete addition, the reactionwas stirred at −78° C. for 6 hours. The reaction then was warmed to 0°C. and carefully poured into ice cold 1M potassium sodium tartrate (1500mL) with rapid stirring, and diluted with EtOAc (1500 mL). Afterstirring for 15 minutes, the layers were separated, and the organiclayers washed with 1M potassium sodium tartrate (1×1000 mL) andsaturated NaCl (1×1000 mL). The organic layers were dried (MgSO₄),filtered, and concentrated in vacuo to provide a 2.5:1 mixture ofdiastereomers plus approximately 10% residual starting aldehyde by crude¹H-NMR. The crude product was chromatographed on a 110 mm×8″ column with3/7/0.4 EtOAc/hexane/MeOH to provide, after pooling and concentration invacuo of the desired lower R_(f) diastereomer containing fractions,Intermediate 71 (8.1 gm, 57%) as an orange oil.

[0301]¹H-NMR (400 MHz, CDCl₃) δ: 7.34-7.23 (m, 5H), 6.86 (m, 3H), 6.79(d, 1H), 3.79 (s, 3H), 3.65 (dd, 1H), 3.62 (s, 2H), 3.58 (dd, 1H), 3.29(dd, 1H), 3.10 (d, 1H), 2.53 (dd, 1H), 2.07 (d, 1H), 1.35 (s, 9H), 1.12(d, 3H), 0.45 (s, 3H).

Intermediate 725-[(4R)-4-((1S)-1-Hydroxyethyl)-4-methyl-1-benzyl-pyrrolidin-3-yl]-2-methoxyphenol

[0302] To a stirred solution of Intermediate 71 (2.3 gm, 5.8 mmol) inCH₂Cl₂ (18 mL) at 0° C. under a drying tube was added trifluoroaceticacid (2.7 mL, 35 mmol). The cooling bath was removed and the reactionallowed to warm to room temperature, then stirred for 3.5 hours. Thereaction was concentrated by rotary evaporator to remove excesstri-fluoroacetic acid, redissolved in CH₂Cl₂ (50 mL), then washed with10% Na₂CO₃ (2×50 mL) and saturated NaCl (1×50 mL). The organic layerswere dried (MgSO₄), filtered, and concentrated in vacuo to provideIntermediate 72 as a white foam (1.9 gm, 96%).

[0303]¹H-NMR (400 MHz, CDCl₃) δ: 7.36-7.20 (m, 5H), 6.82 (s, 1H), 6.77(d, 1H), 6.66 (d, 1H), 5.57 (s, 1H), 3.83 (s, 3H), 3.70-3.56 (m, 4H),3.30 (dd, 1H), 3.13 (d, 1H), 2.55 (dd, 1H), 2.04 (d, 1H), 1.12 (d, 3H),0.45 (s, 3H).

Intermediate 73(1R)-1-{(3R)-4-(3-(tert-Butoxy)-4-methoxyphenyl]-3-methylpyrrolidin-3-yl}ethan-1-ol

[0304] Prepared from Intermediate 71 (1 gm, 2.53 mmol) by. thedebenzylation procedure of Intermediate 31 to give 775 mg ofIntermediate 73.

[0305]¹H-NMR (400 MHz, CDCl₃) δ: 6.92-6.79 (m, 3H), 3.78 (s, 3H),3.51-3.42 (m, 4H), 3.29 (dd, 1H), 2.77 (d, 1H), 1.35 (s, 9H), 1.17 (d,3H), 0.62 (s, 3H).

Intermediate 74 R¹=H Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylate

[0306] Hunig's Base Mediated Acylation Procedure

[0307] To a cooled (0° C.), stirred solution of Intermediate 70 (670 mg,2.67 mmol) and Hunig's base (1.4 mL, 8.0 mmol) in dry CH₂Cl₂ (10 mL),1,4-dioxane (5 mL), and MeOH (1 mL) was added methyl chloroformate (0.41mL, 5.3 mmol) via syringe under a nitrogen atmosphere. The resultingsolution was allowed to stir at 0° C. for 1 hour, then diluted withCH₂Cl₂ (90 mL), washed successively with 1 N aqueous HCl (2×20 mL) andbrine (20 mL), and dried (Na₂SO₄), filtered, and concentrated in vacuo.The residue (737 mg) was dissolved in THF (3 mL) and water (2 mL), thentreated with a solution of LiOH (112 mg, 2.67 mmol in 2 mL water) atroom temperature. After stirring for 4 hours, the reaction was dilutedwith EtOAc (100 mL) and washed successively with 1 N aqueous HCl (2×50mL), saturated aqueous NaHCO₃ (30 mL) and brine (30 mL), then dried(Na₂SO₄), filtered, and concentrated in vacuo. The residue was purifiedvia radial chromatography (4 mm plate with 3% MeOH in CH₂Cl₂) to provideIntermediate 74 as a light tan foam (250 mg, 30%).

[0308]₁H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.84 (d, 1H), 6.78(d, 1H), 6.72 (dd, 1H), 5.57 (d, 1H), 3.90-3.54 (m, 1H), 3.30 (d, 0.5H),3.20 (d, 0.5H), 1.35 (br d, 1H), 1.14 (t, 3H), 0.75 (s, 3H). LRMS(Electrospray, negative): m/z 308.6 (m−1). LRMS (Electrospray,positive): m/z 310.5 (m+1).

Intermediate 75

[0309] From Intermediate 57 via debenzylation procedure of Intermediate31 and Hunig's Base Mediated Acylation procedure of Intermediate 74.

[0310] LRMS (Electrospray, negative): m/z 308.6 (m−1). LRMS(Electrospray, positive): m/z 310.5 (m+1).

Intermediate 76 (2R)-2-Hydroxyhexanoic acid

[0311] To a cooled (0° C.), stirred solution of D-norleucine (500 mg,3.81 mmol) in 10 mL of 1N aqueous sulfuric acid was added sodium nitrite(421 mg, 6.10 mmol) in 3 mL of water dropwise over a 20-minute period.The reaction mixture was allowed to slowly warm to room temperature overa 16-hour period. The mixture then was extracted with EtOAc (2×25 mL),dried (Na₂SO₄), and concentrated to yield 200 mg (40%) of a white waxysolid.

[0312]¹H NMR (400 MHz, CDCl₃) δ: 4.28 (dd, 1H), 1.92-1.81 (m, 1H),1.76-1.64 (m, 1H), 1.51-1.29 (m, 4H), 0.92 (t, 3H). LRMS (Electrospray,negative): Da/e 131.1 (m-1).

Intermediate 77 (1R)-1-(Chlorocarbonyl)pentyl acetate

[0313] Acylation/Hydrolysis/Acid Chloride Formation Procedure

[0314] To a cooled (0° C.) solution of Intermediate 76 (200 mg, 1.51mmol) and Hunig's base (657 mL, 3.78 mmol) in CH₂Cl₂ (6 mL) was addedacetyl chloride (215 μL, 3.03 mmol) by syringe. The resulting mixturewas allowed to slowly warm to room temperature over a 16 hour period.The reaction mixture then was washed with 1N HCl (2×20 mL), dried(Na₂SO₄), and concentrated to an orange brown oil, which by NMR wasshown to be the bis-acylated material. To this material was added 5 mLof 4:1 THF:water, and the mixture stirred for 16 hours at roomtemperature, extracted with EtOAc, dried (Na₂SO₄), and concentrated to186 mg (71%) of an orange oil. NMR and mass spectrometry confirmed theacetoxy acid. To this material in 5 mL of CH₂Cl₂ was added oxalylchloride (1.07 mL, 2.14 mmol, 2M solution in CH₂Cl₂) and a drop of DMF.The mixture was stirred at room temperature for 4 hours, thenconcentrated under reduced pressure to afford Intermediate 77.

[0315]¹H NMR (400 MHz, CDCl₃) δ: 5.17 (dd, 1H), 2.18 (s, 3H), 2.04-1.86(m, 2H), 1.50-1.30 (m, 4H), 0.93 (t, 3H).

Intermediate 78 (Chlorocarbonyl)(4-fluorophenyl)methyl acetate Preparedvia the acylation/hydrolysis/acid chloride formation procedure ofIntermediate 77 from 2-(4-fluorophenyl)-2-hydroxyacetic acid.

[0316]¹H NMR (400 MHz, CDCl₃) δ: 7.48 (q, 2H), 7.14 (t, 2H), 6.06 (s,1H), 2.21 (s, 3H).

Intermediate 79 (Chlorocarbonyl)cyclopropyl acetate

[0317] Prepared via the acylation/hydrolysis/acid chloride formationprocedure of Intermediate 77 from 1-hydroxycyclopropanecarboxylic acid.

[0318]¹H NMR (400 MHz, CDCl₃) δ: 2.13 (s, 3H), 1.89-1.84 (m, 2H),1.46-1.42 (m, 2H).

Intermediate 80 (1S)-1-(Chlorocarbonyl)-2-methylbutyl acetate

[0319] Prepared via the acylation/hydrolysis/acid chloride formationprocedure of Intermediate 77 from (2S)-2-hydroxy-3-methylpentanoic acid.

[0320]¹H NMR (400 MHz, CDCl₃) δ: 5.01 (d, 1H), 2.24-2.17 (m, 1H), 2.17(s, 3H), 1.57-1.47 (m, 1H), 1.39-1.28 (m, 1H), 1.03 (d, 3H), 0.94 (t,3H).

Intermediate 81 (1S)-1-(Chlorocarbonyl)-3-methylbutyl acetate

[0321] Prepared via the acylation/hydrolysis/acid chloride formationprocedure of Intermediate 77 from (2S)-2-hydroxy-4-methylpentanoic acid.

[0322]¹H NMR (400 MHz, CDCl₃) δ: 5.12 (d, 1H), 2.16 (s, 3H), 1.88-1.75(m, 3H), 0.97 (dd, 6H).

Intermediate 82 (1R)-1-(Chlorocarbonyl)-2-phenylethyl acetate

[0323] Prepared via the acylation/hydrolysis/acid chloride formationprocedure of Intermediate 77 from (2R)-2-hydroxy-3-phenylpropanoic acid.

[0324]¹H NMR (400 MHz, CDCl₃) δ: 7.38-7.21 (m, 5H), 5.33 (dd, 1H), 3.33(dd, 1H), 3.18 (dd, 1H), 2.11 (s, 3H).

Intermediate 83 (1S)-1-(Chlorocarbonyl)-2-phenylethyl acetate

[0325] Prepared via the acylation/hydrolysis/acid chloride formationprocedure of Intermediate 77 from (2S)-2-hydroxy-3-phenylpropanoic acid.

[0326]¹H NMR (400 MHz, CDCl₃) δ: 7.38-7.21 (m, 5H), 5.33 (dd, 1H), 3.33(dd, 1H), 3.18 (dd, 1H), 2.11 (s, 3H).

Intermediate 84 (4-Chlorophenyl)(hydroxyimino)methylamine

[0327] A solution of 4-chlorobenzonitrile (10 g, 0.073 mole),hydroxylamine hydrochloride, and NaOH (3.5 g, 0.087 mole) in ethanol(300 mL) and water (80 mL) was refluxed for 10 hours, then concentratedunder reduced pressure. The resulting off-white solid was taken up inwater/4:1 EtOAc:CH₂Cl₂. The organic layers were isolated, washed oncewith water, dried (Na₂SO₄), and concentrated to 10.4 g of a white solid(84%).

[0328]¹H NMR (DMSO-d₆, 400 MHz) δ: 9.71 (s, 1H), 7.66 (d, 2H), 7.41 (d,2H), 5.85 (br s, 2H).

Intermediate 85 [3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl acetate

[0329] To a chilled (0° C.) solution of Intermediate 84 (4.5 g, 0.026mole) in dry pyridine (20 mL) was added acetoxyacetyl chloride (6 mL,0.056 mole) dropwise over a one-hour period. After the addition wascomplete, the mixture was heated at 90° C. for three hours, then allowedto cool to room temperature. The pyridine was removed under reducedpressure, and the resulting dark oily material was taken up in CH₂Cl₂and filtered through GF/F filter paper. The filtrate was washed withbrine (2×100 mL), dried (Na₂SO₄), and concentrated. Biotage purification(40M cartridge, 20% EtOAc/hexane) afforded 1.93 g of Intermediate 85 asa white solid (29%).

[0330]¹H NMR (400 MHz, CDCl₃) δ: 8.01 (d, 2H), 7.46 (d, 2H), 5.35 (s,2H), 2.21 (s, 3H).

Intermediate 86 [3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]methan-1-ol

[0331] To a solution of Intermediate 85 (1 g, 3.96 mmol) in MeOH (50 mL)was added aqueous K₂CO₃ (0.56 M, 7 mL, 3.96 mmol) and the mixturestirred at room temperature for two hours. The solvents then wereremoved under reduced pressure, and the residue taken up in EtOAc (75mL), washed with water (2×75 mL), dried (Na₂SO₄), and concentrated to820 mg (98%) of Intermediate 86 as a white solid.

[0332]¹H NMR (400 MHz, CDCl₃) δ: 8.02 (d, 2H), 7.47 (d, 2H), 4.97 (s,2H), 2.52 (br s, 1H).

Intermediate 87 [3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]methylmethylsulfonate

[0333] Prepared via the mesylation procedure of Intermediate 90.

[0334]¹H NMR (400 MHz, CDCl₃) δ: 8.02 (d, 2H), 7.47 (d, 2H), 5.49 (s,2H), 3.24 (s, 3H).

Intermediate 88 3-[4-(Trifluoromethyl)phenyl]prop-2-yn-1-ol

[0335] Palladium Catalyzed Coupling Procedure

[0336] A solution of 4-iodobenzotrifluoride (5 g, 0.018 mole), propargylalcohol (1.07 ml, 0.018 mole), copper(I) iodide (17.5 mg, 0.092 mmol),and bis-triphenylphosphinepalladium(II) chloride (129 mg, 0.184 mmol) in50 mL of diethylamine was stirred at room temperature for several hours.The diethylamine then was removed under reduced pressure and the residuetaken up in CH₂Cl₂ (150 mL). This was washed with 1N HCl (3×150 mL),dried (Na₂SO₄), and concentrated to 3.1 g of Intermediate 88 as anorange/brown oil (84%).

[0337]¹H NMR (400 MHz, CDCl₃) δ: 7.55 (q, 4H), 4.52 (d, 2H), 1.74 (br s,1H).

Intermediate 89 3-(4-Florophenyl)prop-2-yn-1-ol

[0338] Prepared via the procedure of Intermediate 88.

[0339]¹H NMR (400 MHz, CDCl₃) δ: 7.42 (q, 2H), 7.01 (t, 2H), 1.70 (t,1H).

Intermediate 90 3-Phenylprop-2-ynyl methylsulfonate

[0340] Mesylation Procedure

[0341] To a solution of 3-phenyl-2-propyn-1-ol (100 g, 0.757 mole) andEt₃N (158 mL, 1.13 mole) in 3 liters of dry CH₂Cl₂ chilled to 5° C. wasadded methanesulfonyl chloride (59 mL, 0.757 mole) via an additionfunnel, maintaining the internal temperature about 5° C. (additioncomplete after approximately 45 minutes). After one hour at 5° C., TLCindicated most of starting material was consumed. One mL ofmethanesulfonyl chloride was added, and the reaction mixture stirred foran additional 30 minutes at 5° C. TLC indicated complete consumption ofstarting material. The mixture then was washed with 1N HCl (3×250 mL),dried (Na₂SO₄), and concentrated to yield 113 g of Intermediate 90 as ayellow liquid (71%).

[0342]¹H NMR (400 MHz, CDCl₃) δ: 7.48-7.45 (m, 2H), 7.39-7.34 (m, 3H),5.09 (s, 2H), 3.16 (s, 3H).

Intermediate 91 3-(4-Fluorophenyl)prop-2-ynyl methylsulfonate

[0343] Prepared from Intermediate 89 via the mesylation method ofIntermediate 90.

[0344]¹H NMR (400 MHz, CDCl₃) δ: 7.47-7.44 (q, 2H), 7.04 (t, 2H), 5.07(s, 2H), 3.15 (s, 3H).

Intermediate 92 3-[4-(Trifluoromethyl)phenyl]prop-2-ynylmethyl-sulfonate

[0345] Prepared from Intermediate 88 via the mesylation method ofIntermediate 90.

[0346]¹H NMR (400 MHz, CDCl₃) δ: 7.62-7.56 (m, 4H), 5.09 (s, 2H), 3.16(s, 3H).

EXAMPLE 3

[0347] Preparation of four stereoisomers from reduction of Intermediate36. Sodium borohydride (2.0 mmol, 0.075 g) was added to Intermediate 36(1.3 mmol, 0.50 g) dissolved in 10 mL of ethanol. The complete reactionwas dried in vacuo after 1 hour. The resulting oil was extracted threetimes with EtOAc from water, then the combined extracts were washed withbrine and dried over MgSO₄. The mixture of two racemates was obtained asan oil.

[0348]¹H NMR δ: 6.80 (d, 1H); 6.67 (d, 2H); 4.72 (bd, 1H); 3.86-3.95(bm, 1H); 3.83 (s, 3H); 3.64-3.78 (bm, 1H); 3.74 (s, 3H); 3.33 (dd, 1H);2.16 (d, 3H); 1.79-1.92 (bm, 4H); 1.59-1.63 (bm, 2H); 1.01 (sd, 3H).

[0349] The mixture of racemates was dissolved in 50% acetonitrile and50% water at a concentration of 50 mg/mL and purified in portions on aC-18 column (250×10 mm) using a water/acetonitrile/0.5% TFA gradient.Appropriate fractions were collected, combined, and dried to oils.

[0350]¹H NMR for minor racemate δ: 6.75-6.82 (bm, 3H); 4.75 (bd, 1H);3.83 (s, 3H); 3.64-3.81 (bm, 1H); 3.74 (s, 3H); 3.54-3.61 (bm, 2H); 3.28(dd, 1H); 1.81-1.94 (bm, 5H); 1.58-1.65 (bm, 4H); 1.15 (dd, 3H); 0.75(s, 3H). ¹H NMR for the major racemate δ: 6.76-6.83 (bm, 3H); 4.74 (bd,1H); 3.77-3.89 (bm, 1H); 3.83 (s, 3H); 3.73 (s, 3H); 3.65 (quin, 1H);3.25-3.32 (bm, 3H); 1.77-1.96 (bm, 7H); 1.58-1.61 (bm, 2H); 1.13 (d,3H); 0.92 (s, 3H)

[0351] Chiral Separation of the Alcohols

[0352] Two columns were required to separate the four diastereomers byHPLC. The first dextrose-based column (8×30 cm) was used to separate theR,R,S isomer from the others. Ten mL (7.1 mg/mL stock solution) of crudemixture in column buffer was introduced then eluted at 1 mL/min withisocratic hexanes (85%) and isopropanol (15%), collecting theappropriate fractions. The remaining diastereomers were purified on adifferent dextrose-based column (10×50 cm). Again, 10 mL (7.1 mg/mLstock solution) was injected, then eluted at 1 mL/min with isocratichexanes (95%) and isopropanol (5%). The appropriate fractions werecollected, combined and dried to oils.

EXAMPLE 4 R¹=2-indanyl; R³=CO₂CH₃trans-(±)-3-(1-Hydroxyethyl)-4-[3-(indan-2-yloxy)-4-methoxyphenyl]-3-methylpyrrolidine-1-carboxylicacid methyl ester (2 carbinol diastereomers)

[0353] A solution of Intermediate 35 (racemic) (300 mg, 0.71 mmol, 1 eq)in ethanol (10 mL) was treated with sodium borohydride (54 mg, 1.42mmol, 2 eq). The mixture was stirred 10 min at room temperature, treatedwith 1 N HCl (50 mL), and extracted with EtOAc (3×25 mL). The combinedorganic extracts were washed with 1 N HCl (25 mL), water, sat. NaHCO₃(25 mL), water (25 mL), and brine (25 mL), dried over Na₂SO₄, andconcentrated in vacuo. A portion of the crude residue was purified byHPLC (Vydac 20×250 mm C18 “Protein and Peptide” column, 8 min. gradientof 50-75% acetonitrile in water with each solvent containing 0.05% TFA,flow rate of 20 mL/min) to yield the separated diastereomers in a 2:1ratio as colorless syrups (75 and 37 mg respectively, in order ofelution from column).

[0354] Isomer 1: ¹H NMR (300 MHz, CDCl₃) δ: 7.24-7.15 (m, 4H), 6.83 (brs, 3H), 5.21-5.12 (m, 1H), 3.91-3.59 (m, 3H), 3.81 (s, 3H), 3.73 (s,3H), 3.40-3.18 (m, 7H), 1.14 (d, J=6.3 Hz, 3H), 0.94 (s, 3H).

[0355] Isomer 2: ¹H NMR (300 MHz, CDCl₃) δ: 7.23-7.15 (m, 4H), 6.85-6.82(m, 3H), 5.22-5.10 (m, 1H), 3.89-3.67 (m, 3H), 3,81 (s, 3H), 3,75 (s,3H), 3,64-3.52 (m, 2H), 3.40-3.15 (m, 5H), 1.20-1.13 (m, 3H), 0.78 (s,3H).

[0356] The compounds of Examples 5 and 6 were prepared in the samemanner as Example 4:

EXAMPLE 5 R¹=2-norbornyl; R³=CO₂CH₃ trans4-[3-Exo-(Bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]-3-(1-hydroxyethyl)-3-methylpyrrolidine-1-carboxylicacid methyl ester (2 carbinol diastereomers)

[0357] Intermediate 38 was reduced and separated as above to give twoisomers:

[0358] Isomer 1: ¹H NMR (300 MHz, CDCl₃) δ: 6.82-6.72 (m, 3H), 4.15 (brs, 1H), 3.88-3.59 (m, 3H), 3.87 (s, 3H), 3.73 (s, 3H), 3.32-3.24 (m,3H), 2.50-2.47 (m, 1H), 2.34-2.28 (m, 1H), 1.77-1.50 (m, 5H), 1.21-1.12(m, 6H), 0.92 (s, 3H).

[0359] Isomer 2: ¹H NMR (300 MHz, CDCl₃) δ: 6.82-6.72 (m, 3H), 4.19-4.15(m, 1H), 3.85-3.54 (m, 5H), 3.83 (s, 3H), 3.74 (s, 3H), 3.30/3.23 (2 d,J=10.4/10.4 Hz, 1H), 2.49-2.46 (m, 1H), 2.32 (br s, 1H), 1.76-1.70 (m,2H), 1.65-1.44 (m, 3H), 1.21-1.14 (m, 6H), 0.75 (s, 3H).

EXAMPLE 6 R¹=PhCH₂CH₂CH(CH₃); R³=CO₂CH₃trans-3-(1-Hydroxyethyl)-4-[4-methoxy-3-(1-methyl-3-phenylpropoxy)phenyl]-3-methylpyrrolidine-1-carboxylicacid methyl ester (2 carbinol diastereomers)

[0360] Intermediate 39 was reduced and separated as above to give twoisomers:

[0361] Isomer 1: ¹H NMR (300 MHz, CDCl₃) δ: 7.30-7.25 (m, 3H), 7.22-7.15(m, 3H), 6.85-6.69 (m, 3H), 4.34-4.27 (m, 1H), 3.87-3.54 (m, 3H), 3.84(s, 3H), 3.73/3.72 (2 s, 3H), 3.31-3.20 (m, 3H), 2.83-2.75 (m, 2H)2.18/2.08 (m, 1H), 1.95-1.84 (m, 1H), 1.34/1.31 (2 s, 3H), 1.12 (d,J=6.3 Hz, 3H), 0.89 (br s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ: 156.0, 150.3,147.8, 142.2, 131.3/131.1, 128.9, 128.8, 126.2, 121.7, 117.1, 112.5,77.6, 75.3/75.1, 74.1/74.0, 56.3, 56.2/55.8, 52.9, 52.0/51.5/51.2,49.9/49.1, 38.5/38.4, 32.2, 20.3, 19.0/18.9, 14.6/14.5.

[0362] Isomer 2: ¹H NMR (300 MHz, CDCl₃) δ: 7.29-7.24 (m, 2H), 7.20-7.14(m, 3H), 6.84-6.69 (m, 3H), 4.35-4.24 (m, 1H), 3.85/3.84 (2 s, 3H)3.83-3.45 (m, 5H) 3.75 (s, 3H), 3.31-3.23 (m, 1H), 2.88-2.76 (m, 2H),2.21-2.07 (m, 1H), 1.95-1.83 (m, 1H), 1.34/1.32 (2 s, 3H), 1.15-1.11 (m,3H), 0.73 (br s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ: 156.1, 149.9, 147.4,142.3, 129.5/129.4, 128.9, 128.7, 126.2, 122.1/121.8, 117.9/117.7/117.4,112.0, 77.6, 75.3/75.0/74.9, 69.4/69.3, 56.3, 53.2, 53.1,49.5/49.3/49.1/48.6, 46.5/46.0, 38.5/38.4/38.3, 32.1, 20.3, 20.0, 17.7.

[0363] The following compounds were prepared from chiral freepyrrolidine Intermediate 68.

EXAMPLE 7 R¹=C₅H₉; R³=COCH₂OCH₂Ph1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(phenylmethoxy)ethan-1-one

[0364] N-Acylation Procedure

[0365] To a stirred solution Intermediate 68 (42.6 mg, 0.13 mmol) in1,4-dioxane (0.4 mL) was added, successively, aqueous K₂CO₃ (0.8 mL of0.65 M, 4 eq.) and a solution of the acid chloride (R₃—Cl) (21 μL, 0.13mmol) in 1,4-dioxane (0.4 mL) at room temperature. The resultingsolution was allowed to stir at room temperature for 4 hours. Thereaction was diluted with EtOAc (30 mL), then washed successively withwater (20 mL) and brine (20 mL), dried (MgSO₄), filtered, andconcentrated in vacuo to provide Example 7 as a slightly tan foam (46.5mg, 99%).

[0366]¹H NMR (400 MHz, CDCl₃) δ: mixture of rotomers): 7.40-7.31 (m,5H), 6.80-6.72 (m, 3H), 4.73 (c, 1H), 4.67 (s, 2H), 4.14 (s, 2H), 3.82(s, 3H), 3.79-3.45 (m, 5H), 3.22 (d, 1H), 1.92-1.80 (c, 6H), 1.61-1.55(c, 2H), 1.14 (dd, 3H), 0.73 (d, 3H). LRMS (Electrospray, positive):Da/e 468.4 (m+1).

EXAMPLE 8 R¹=C₅H₉; R³=COCH₂OH1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyethan-1-one

[0367] Example 7 (35 mg, 75 μmol) was subjected to the debenzylationprocedure of Intermediate 31 to give Example 8 (24 mg, 84%).

[0368]¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 6.91-6.82 (m, 3H),4.83 (c, 1H), 4.22 (c, 1H), 3.87-3.22 (m, 11H), 1.93-1.73 (m, 6H),1.69-1.59 (m, 2H), 1.11 (dd, 3H), 0.75 (br s, 3H). LRMS (Electrospray,positive): Da/e 378.4 (m+1).

EXAMPLE 9 R¹=C₅H₉; R³=COCH₂CH₂N(H)CO₂CH₂PhN-{3-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-3-oxopropyl}(phenylmethoxy)carboxamide

[0369] Prepared from Intermediate 68 via the acylation procedure ofExample 7. The p-nitrophenylester of N-Cbz-beta-alanine was used inplace of the acid chloride.

[0370]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.38-7.28 (m, 5H),6.92-6.83 (m, 3H), 5.06 (c, 2H), 4.86 (s, 2H), 4.84 (c, 1H), 3.81-3.27(m, 10H), 2.59 (c, 2H), 1.98-1.69 (c, 6H), 1.64-1.57 (c, 2H), 1.09 (d,3H), 0.73 (d, 3H). LRMS (Electrospray, positive): Da/e 525.3 (m+1).

EXAMPLE 10 R¹=C₅H₉; R³=COCH₂CH₂NH₂1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-3-amino-propan-1-one

[0371] Prepared from Example 9 via the debenzylation procedure ofIntermediate 31.

[0372]¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 6.91-6.79 (m, 3H),4.81 (c, 1H), 3.92-3.29 (m, 11H), 3.01 (br s, 2H), 2.61-2.58 (m, 2H),1.95-1.73 (m, 6H), 1.68-1.58 (m, 2H), 1.10 (dd, 3H), 0.76 (d, 3H). LRMS(Electrospray, positive): Da/e 391.4 (m+1).

EXAMPLE 11 R¹=C₅H₉; R³=COCH₂CH₂CO₂CH₂Ph Phenylmethyl4-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-4-oxobutanoate

[0373] Prepared from Intermediate 68 via the acylation procedure ofExample 7.

[0374]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.41-7.31 (m, 5H),6.84-6.75 (m, 3H), 5.14 (d, 2H), 4.74 (c, 1H), 3.94-3.44 (m, 8H), 3.27(d, 1H), 2.80-2.73 (m, 2H), 2.67-2.58 (m, 2H), 1.96-1.81 (m, 6H),1.68-1.56 (m, 2H), 1.15 (dd, 3H), 0.75 (d, 3H). LRMS (Electrospray,positive): Da/e 510.3 (m+1).

EXAMPLE 12 R¹=C₅H₉; R³=COCH₂CH₂CO₂H4-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-4-oxo-butanoicacid

[0375] Prepared from Example 11 via the debenzylation procedure ofIntermediate 31.

[0376]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.80-6.72 (m, 3H),4.74 (c, 1H), 3.98-3.54 (m, 10H), 3.40 (d, 1H), 3.24 (d, 1H), 2.69 (c,2H), 1.95-1.74 (m, 6H), 1.69-1.51 (m, 2H), 1.14 (dd, 3H), 0.74 (d, 3H).LRMS (Electrospray, positive): Da/e 420.3 (m+1).

EXAMPLE 13 R¹=C₅H₉; R³=COCH₂N(H)CO₂CH₂PhN-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoethyl}(phenylmethoxy)carboxamide

[0377] Prepared from Intermediate 68 via the acylation procedure ofExample 7. The p-nitrophenylester of N-Cbz-glycine was used in place ofthe acid chloride.

[0378]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.25 (m, 5H),6.92-6.81 (m, 3H), 5.11 (s, 2H), 4.87 (s, 2H), 4.82 (c, 1H), 4.11-3.28(m, 9H), 1.95-1.70 (m, 6H), 1.65-1.55 (m, 2H), 1.10 (br s, 3H), 0.76 (brs, 3H). LRMS (Electrospray, positive): Da/e 511.6 (m+1).

EXAMPLE 14 R¹=C₅H₉; R³=COCH₂NH₂1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-amino-ethan-1-one

[0379] Prepared from Example 13 via the debenzylation procedure ofIntermediate 31.

[0380]¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 6.91-6.82 (m, 3H),4.80 (c, 1H), 3.91-3.28 (m, 11H), 1.90-1.75 (m, 6H), 1.66-1.57 (m, 2H),1.09 (dd, 3H), 0.74 (d, 3H). LRMS (Electrospray, positive): Da/e 377.2(m+1).

EXAMPLE 15 R¹=C₅H₉; R³=CO-4-Methyl-piperazine3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl-4-methyl-piperazinylketone

[0381] Intermediate 68 (30.2 mg, 94 mmol) was dissolved in1,2-dichloroethane (400 μL) and cooled to 0° C., then carbonyldiimidazole (16 mg, 94 μmol) was added. The reaction was stirred at 0°C. for 1.5 hours, followed by the addition of 1-methylpiperazine (21 μL,180 μmol). The solution was heated to 80° C. for 60 hours. Aftercooling, the reaction mixture was diluted with CH₂Cl₂ and washed threetimes with 6% NaHCO₃, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was chromatographed on SiO₂ with EtOAc (15.5 mg).

[0382]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.83-6.78 (m, 3H),4.76 (c, 1H), 4.06-3.77 (m, 18H), 3.61 (q, 1H), 3.39 (br s, 1H),1.93-1.78 (m, 6H), 1.63-1.57 (m, 2H), 1.15 (br s, 3H), 0.81 (br s, 3H).LRMS (Electrospray, positive): Da/e 446.4 (m+1).

EXAMPLE 16 R¹=C₅H₉; R³=CO—N-morpholine3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinylmorpholin-4-yl ketone

[0383] Prepared from Intermediate 68 using morpholine andcarbonyldiimidazole as a coupling reagent by the procedure set forth inExample 15.

[0384]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.84-6.77 (m, 3H),4.76 (c, 1H), 3.88-3.52 (m, 12H), 3.41 (dd, 1H), 3.38 (dd, 1H), 3.28(dd, 1H), 3.25 (dd, 1H), 3.10 (d, 1H), 1.95-1.81 (m, 6H), 1.62-1.54 (m,2H), 1.15 (d, 3H), 0.75 (s, 3H). LRMS (Electrospray, positive): Da/e433.3 (m+1).

EXAMPLE 17 R¹=C₅H₉; R³=COCH₂O-Menthol; (1S)-carbinol isomer1-[3-((1S)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-[(2S,1R,5R)-5-methyl-2-(methylethyl)cyclohexyloxy]-ethan-1-one

[0385] Prepared from the S-carbinol isomer Intermediate 69 by theHunig's base mediated acylation procedure of Intermediate 69.

[0386]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.82-6.75 (m, 3H),4.74 (c, 1H), 4.19 (dd, 1H), 4.04 (dd, 1H), 3.92-3.76 (m, 5H), 3.47-3.19(m, 5H), 2.26 (c, 1H), 2.13 (c, 1H), 1.94-1.80 (m, 6H), 1.65-1.53 (m,4H), 1.51-1.19 (m, 4H), 1.14 (d, 3H), 0.95-0.84 (m, 9H), 0.79 (d, 3H).LRMS (Electrospray, positive): Da/e 516.3 (m+1).

EXAMPLE 18 R¹=C₅H₉; R³=CO-4-(2-methylthiazole)3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl2-methyl-(1,3-thiazol-4-yl)ketone

[0387] Prepared from Intermediate 68 via the EDCI coupling procedure ofExample 27 from 2-methyl-1,3-thiazole-4-carboxylic acid.

[0388]¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 7.98 (dd, 1H),6.92-6.82 (m, 3H), 4.84 (c, 1H), 4.27 (t, 0.5H), 4.16 (t, 0.5H), 4.08(t, 0.5H), 3.96 (d, 0.5H), 3.85-3.4 (m, 7H), 2.72 (dd, 3H), 1.88-1.72(m, 6H), 1.68-1.56 (m, 2H), 1.14 (dd, 1.5H), 1.08 (dd, 1.5H), 0.82 (d,1.5H), 0.73 (d, 1.5H). LRMS (Electrospray, positive): Da/e 445.4 (m+1).

EXAMPLE 19 R¹=C₅H₉; R³=SO₂-3-pyridyl3-{[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]sulfonyl}-pyridine

[0389] To a stirred solution of Intermediate 68 (32 mg, 0.1 mmol) indioxane (0.3 mL) were added, successively, aqueous K₂CO₃ (0.6 mL of 0.65M, 4 eq.) and a solution of the R³-sulfonyl chloride (26 mg, 0.12 mmol)in dioxane (0.3 mL) at room temperature. The resulting solution wasallowed to stir at room temperature for 2 hours. The reaction wasdiluted with 1:1 hexanes:EtOAc (30 mL) and washed successively withwater (20 mL) and brine (20 mL), then dried (MgSO₄), filtered, andconcentrated in vacuo to provide Example 19 as a slightly orange foam(36 mg, 78%).

[0390]¹H NMR (400 MHz, CDCl₃) δ: 9.11 (d, 1H, J=2.2 Hz), 8.83 (dd, 1H,J=1.6, 4.8 Hz), 8.17 (ddd, 1H, J=1.5, 2.4, 8.1 Hz), 7.50 (ddd, 1H,J=0.8, 4.9, 8.0 Hz), 6.74 (d, 1H, J=8.5 Hz), 6.68 (d, 1H, J=2.1 Hz),6.62 (dd, 1H, J=2.1, 8.3 Hz), 4.70 (c, 1H), 3.80 (s, 3H), 3.66-3.62 (m,2H), 3.51-3.43 (m, 3H), 3.24 (d, 1H, J=13.3 Hz), 1.91-1.62 (m, 6H),1.60-1.55 (m, 2H), 1.08 (d, 3H, J=6.4 Hz), 0.62 (s, 3H). LRMS(Electrospray, positive): Da/e 461.2 (m+1).

EXAMPLE 20 R¹=2-indanyl; R³=COCH₂OCH₂Ph1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yl-oxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(phenylmethoxy)ethan-1-one

[0391] Prepared from Intermediate 51 (50 mg, 0.14 mmol) by the Hunig'sbase acylation procedure of Intermediate 74 using benzyloxyacetylchloride (22.5 μL, 0.14 mmol) to provide Example 20 as a clear oil (48mg, 68%).

[0392]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.41-7.16 (m, 9H),6.84-6.79 (m, 3H), 5.17 (c, 1H), 4.66 (d, 2H), 4.19-4.11 (m, 2H), 3.96(dd, 0.5H), 3.83-3.54 (m, 7H), 3.47 (d, 0.5H), 3.38-3.29 (m, 2H),3.24-3.17 (m, 3H), 1.57 (br t, 1H), 1.15 (dd, 3H), 0.75 (s, 3H). LRMS(Electrospray, positive): Da/e 516.8 (m+1).

EXAMPLE 21 R¹=2-indanyl; R³=COCH₂OH1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yl-oxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyethan-1-one

[0393] Prepared from Example 20 via the debenzylation procedure ofIntermediate 31.

[0394]¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 7.24-7.18 (m, 2H),7.14-7.12 (m, 2H), 6.92-6.86 (m, 3H), 5.20 (c, 1H), 4.27-4.14 (m, 2H),3.90-3.50 (m, 6H), 3.41 (d, 1H), 3.34-3.24 (m, 4H), 3.13-3.08 (m, 2H),1.12 (dd, 3H), 0.77 (br s, 3H). LRMS (Electrospray, positive): Da/e426.5 (m+1).

EXAMPLE 22 R¹=2-indanyl; R³=COCO₂CH₃ Methyl2-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoacetate

[0395] Prepared from Intermediate 51 and methyl oxalyl chloride via theHunig's base coupling procedure of Intermediate 74.

[0396]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.82-6.75 (m, 3H),4.74 (c, 1H), 4.01 (d, 1H), 3.98-3.56 (m, 10H), 3.50 (dd, 1H), 1.93-1.84(m, 6H), 1.64-1.56 (m, 2H), 1.45 (dd, 1H), 1.16 (dd, 3H), 0.79 (s,1.5H), 0.75 (s, 1.5H). LRMS (Electrospray, positive): Da/e 406.2 (m+1).

EXAMPLE 23 R¹=2-indanyl; R³=COC(CH₃)2N(H)CO₂CH₂PhN-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1,1-dimethyl-2-oxoethyl}(phenylmethoxy)carboxamide

[0397] PyBrOP Coupling Procedure

[0398] To a stirred solution of bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBrOP, 70 mg, 0.15 mmol),N-carbobenzyloxy-2-methylalanine (35.5 mg, 0.15 mmol), and Hunig's base(78 μL, 0.45 mmol) in dry dimethylformamide (1 mL) was addedIntermediate 51 (50 mg, 0.14 mmol) at room temperature under a nitrogenatmosphere. The resulting solution was allowed to stir at roomtemperature for 16 hours, then heated to 70° C. for 5 hours. Thereaction was allowed to cool to room temperature, then concentrated invacuo. The residue was purified via radial chromatography (1 mm platewith 3% MeOH in CH₂Cl₂) to provide Example 23 as a white foam (20 mg,24%).

[0399]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.43-7.15 (m, 9H),6.82-6.62 (m, 3H), 5.64 (br s, 0.5H), 5.51 (br s, 0.5H), 5.15-5.08 (m,3H), 3.97-3.15 (m, 13H), 1.58 (br s, 6H), 1.13 (br d, 3H), 0.68 (br s,3H). LRMS (Electrospray, positive): Da/e 604.9 (m+18).

EXAMPLE 24 R¹=2-indanyl; R³=COC(CH₃)2NH₂1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yl-oxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-amino-2-methylpropan-1-one

[0400] Prepared from Example 23 via the debenzylation procedure ofIntermediate 31.

[0401]¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 7.21-7.16 (m, 2H),7.15-7.12 (m, 2H), 6.94-6.87 (m, 3H), 5.22 (c, 1H), 4.05 (d, 1H), 3.88(c, 1H), 3.77-3.69 (m, 4H), 3.60-3.52 (c, 2H), 3.40-3.29 (c, 2H), 3.22(q, 1H), 3.13-3.09 (c, 2H), 1.37 (d, 6H), 1.13 (br s, 3H), 0.80 (s, 3H).LRMS (Electrospray, positive): Da/e 453.5 (m+1).

EXAMPLE 25 R¹=2-indanyl; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylate

[0402] Prepared from Intermediate 51 via the Hunig's base mediatedacylation procedure of Intermediate 74 using methyl chloroformate.

[0403]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.24-7.16 (m, 4H),6.86-6.82 (m, 3H), 5.18 (c, 1H), 3.85-3.56 (m, 8H), 3.38-3.30 (m, 3H),3.25-3.19 (m, 3H), 1.51 (d, 0.5H), 1.47 (d, 0.5H), 1.16 (t, 3H), 0.77(s, 3H). LRMS (Electrospray, positive): Da/e 426.5 (m+1), 443.3 (m+18).

EXAMPLE 26 R¹=2-indanyl; R³=COCH₂C(CH₃)₂CO₂H4-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2,2-dimethyl-4-oxobutanoicacid

[0404] A thick walled glass tube fitted with a threaded cap was chargedwith Intermediate 51 (20 mg, 0.05 mmol) and 2,2-dimethylsuccinicanhydride (25.8 mg, 0.05 mmol). The tube was sealed, then heated at 150°C. for 30 minutes. The reaction mixture was allowed to cool to roomtemperature to provide Example 26 (containing about 15-20% of the otherregioisomer) as a brown solid (22 mg, 82%).

[0405]¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 7.22-7.20 (m, 2H),7.15-7.12 (m, 2H), 6.96-6.85 (m, 3H), 5.23 (c, 1H), 3.92-3.49 (m, 7H),3.37-3.28 (m, 4H), 3.13-3.09 (m, 2H), 2.73-2.55 (m, 2H), 1.30 (br s,6H), 1.12 (t, 3H), 0.76 (d, 3H). LRMS (Electrospray, negative): Da/e494.5 (m−1).

EXAMPLE 27 R¹=2-indanyl; R³=CO-4-(2-methylthiazole)3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl2-methyl(1,3-thiazol-4-yl) ketone

[0406] EDCI Coupling Procedure

[0407] To a stirred solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42.3 mg,0.214 mmol) in dry CH₂Cl₂ (1 mL) was added2-methyl-1,3-thiazole-4-carboxylic acid (30.7 mg, 0.214 mmol) at roomtemperature under a nitrogen atmosphere. The resulting bright redmixture was allowed to stir for 1 hour, then Intermediate 51 (75 mg,0.204 mmol) was added in one portion. After stirring at room temperatureovernight, the reaction was concentrated at reduced pressure and theresidue purified via radial chromatography (1 mm plate with 3% MeOH inCH₂Cl₂) to provide Example 27 as a clear film (21 mg, 20%).

[0408]¹H NMR (400 MHz, CDCl₃; mixture of rotomers) δ: 7.91 (s, 0.5H),7.88 (s, 0.5H), 7.25-7.20 (m, 2H), 7.18-7.16 (m, 2H), 6.90-6.82 (m, 3H),5.19 (c, 1H), 4.33 (dd, 0.5H), 4.23 (t, 0.5H), 4.15 (d, 0.5H), 4.10 (dd,0.5H), 3.99 (t, 0.5H), 3.85 (d, 0.5H), 3.81 (s, 3H), 3.77-3.58 (m, 3H),3.38-3.31 (m, 2H), 3.24-3.20 (m, 2H), 2.74 (s, 1.5H), 2.71 (s, 1.5H),1.93 (s, 0.5H), 1.61 (d, 0.5H), 1.22 (d, 1.5H), 1.18 (d, 1.5H), 0.86 (s,1.5H), 0.75 (s, 1.5H). LRMS (Electrospray, positive): Da/e 493.6 (m+1).

EXAMPLE 28 R¹=2-indanyl; R³=CO-3-tetrahydrofuranyl3-((1R)-1-Hydroxyethyl)(4S,3R)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylcyclopentyloxolan-3-yl ketone (mixture of 2 diastereomers at the tetrahydrofuranylpoint of attachment)

[0409] Prepared from Intermediate 51 via the Hunig's base couplingprocedure of Intermediate 74 using tetrahydrofuran-3-carbonyl chloride.

[0410]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.20 (m, 2H),7.19-7.16 (m, 2H), 6.86-6.83 (m, 3H), 5.18 (c, 1H), 4.15-4.04 (m, 1H),3.98-3.15 (m, 13H), 2.31-2.09 (m, 2H), 1.75 (br s, 1H), 1.26 (t, 1.5H),1.17 (t, 1.5H), 0.80 (d, 1.5H), 0.78 (s, 1.5H). LRMS (Electrospray,positive): Da/e 466.3 (m+1).

EXAMPLE 29 R¹=2-indanyl; R³=COCH₂N (H) CO₂CH₂PhN-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoethyl}(phenylmethoxy)carboxamide

[0411] Prepared from Intermediate 51 via the PyBrOP coupling procedureof Example 23 using N-benzyloxy-carbonyl glycine.

[0412]¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 7.35-7.20 (m, 9H),6.91-6.88 (m, 3H), 5.22 (br s, 1H), 5.10 (s, 2H), 4.07-3.09 (m, 15H),1.13 (t, 3H), 0.78 (s, 3H).

EXAMPLE 30 R¹=2-indanyl; R³=COCH₂NH₂1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-aminoethan-1-one

[0413] Prepared from Example 29 via the debenzylation procedure ofIntermediate 31.

[0414]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.22-7.19 (m, 2H),7.18-7.15 (m, 2H), 6.84 (d, 1H), 6.81 (d, 2H), 5.17 (c, 1H), 3.96 (dd,0.5H), 3.81-3.43 (m, 9H), 3.37-3.30 (m, 1.5H), 3.23-3.13 (m, 2H), 2.99(br s, 2H), 1.15 (t, 3H), 0.75 (d, 3H). LRMS (Electrospray, positive):Da/e 425.5(m +1).

EXAMPLE 31 R¹=2-indanyl; R³=2-pyridyl(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-(2-pyridyl)pyrrolidin-3-yl]ethan-1-ol

[0415] Aryl Bromide Coupling Procedure

[0416] To a stirred mixture of Intermediate 51 (115 mg, 0.31 mmol) andK₂CO₃ (173 mg, 1.2 mmol) in dry DMF (2 mL) was added 2-bromopyridine(0.12 mL, 1.2 mmol) via syringe at room temperature under a nitrogenatmosphere. The resulting mixture was heated at 90° C. for 22 hours,then allowed to cool to room temperature. The reaction was diluted withwater (60 mL), and extracted with EtOAc (3×30 mL). The combined organicextracts were washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo.

[0417] The residue was purified via flash chromatography on silica gel(100% EtOAc) to provide Example 31 (73.4 mg, 53%).

[0418]¹H NMR (400 MHz, CDCl₃) δ: 8.18 (ddd, 1H), 7.45 (ddd, 1H),7.26-7.21 (m, 2H), 7.19-7.16 (m, 2H), 6.92-6.88 (m, 2H), 6.83 (d, 1H),6.54 (ddd, 1H), 6.40 (d, 1H), 5.17 (c, 1H), 3.86-3.78 (m, 5H), 3.70 (d,1H), 3.67 (d, 1H), 3.38-3.30 (m, 3H). LRMS (Electrospray, positive):Da/e 445.4 (m+1).

EXAMPLE 32 R¹=2-indanyl; R³=3-pyridyl(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-(3-pyridyl)pyrrolidin-3-yl]ethan-1-ol

[0419] Palladium-Catalyzed Coupling Procedure

[0420] To a stirred solution of Intermediate 51 (79.3 mg, 0.22 mmol) andsodium t-butoxide (29 mg, 0.31 mmol) in dry toluene (3 mL) was added,sequentially, 3-bromopyridine (22.9 mL, 0.24 mmol),tris(dibenzylideneacetone)dipalladium(0) (3.9 mg, cat.), and(R)-(+)-1,1′-bi-2-naphthol (5.4 mg, cat.) at room temperature under anitrogen atmosphere. The resulting mixture was heated at 80° C. for 3hours, then allowed to cool to room temperature. The reaction then wasdiluted with EtOAc (40 mL), washed with brine, dried (Na₂SO₄), filtered,and concentrated in vacuo. The residue was purified via flashchromatography on silica gel (40% EtOAc in hexanes) to provide Example32 (72.1 mg, 75%).

[0421]¹H NMR (400 MHz, CDCl₃) δ: 7.98 (d, 1H), 7.91 (d, 1H), 7.24-7.15(m, 4H), 7.11 (dd, 1H), 6.90-6.82 (m, 4H), 5.15 (c, 1H), 3.81-3.72 (m,4H), 3.70-3.62 (m, 4H), 3.35-3.11 (m, 5H), 1.24 (d, 3H), 0.84 (s, 3H).LRMS (Electrospray, positive): Da/e 445.3 (m+1).

EXAMPLE 33 R¹=2-indanyl; R³=2-pyrimidyl(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-pyrimidin-2-ylpyrrolidin-3-yl]ethan-1-ol

[0422] Prepared from Intermediate 51 via the aryl bromide couplingprocedure of Example 31.

[0423]¹H NMR (400 MHz, CDCl₃) δ: 8.34 (dd, 2H), 7.24-7.18 (m, 2H), 7.16(dd, 2H), 6.94-6.84 (m, 2H), 6.82 (c, 1H), 6.48 (t, 1H), 5.16 (c, 1H),4.12-3.75 (m, 7H), 3.64 (br d, 1H), 3.52 (d, 1H), 3.36 (d, 1H), 3.32 (d,1H), 3.24 (t, 1H), 3.20 (t, 1H), 1.23 (d, 3H), 0.83 (s, 3H). LRMS(Electrospray, positive): Da/e 446.4 (m+1).

EXAMPLE 34 R¹=C₅H₉; R³=2-pyridyl(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-(2-pyridyl)pyrrolidin-3-yl]ethan-1-ol

[0424] Prepared from Intermediate 68 via the aryl bromide couplingprocedure of Example 31.

[0425]¹H NMR (400 MHz, CDCl₃) δ: 8.18 (ddd, 1H), 7.46 (ddd, 1H),6.89-6.82 (m, 3H), 6.54 (ddd, 1H), 6.40 (d, 1H), 4.75 (c, 1H), 3.92-3.65(m, 8H), 3.36 (d, 1H), 1.94-1.80 (m, 6H), 1.66-1.55 (m, 2H). LRMS(Electrospray, positive): Da/e 397.4 (m+1).

EXAMPLE 35 R¹=C₅H₉; R³=3-pyridyl(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-(3-pyridyl)pyrrolidin-3-yl]ethan-1-ol

[0426] Prepared from Intermediate 68 via the palladium catalyzedcoupling procedure of Example 32.

[0427]¹H NMR (400 MHz, CDCl₃) δ: 8.00 (d, 1H), 7.93 (d, 1H), 7.12 (dd,1H), 6.86-6.78 (m, 4H), 4.73 (c, 1H) 3.85-3.59 (m, 8H) 3.12 (d, 1H),1.90-1.79 (m, 6H) 1.60-1.54 (m, 2H), 1.22 (d, 3H), 0.82 (s, 3H). LRMS(Electrospray, positive): Da/e 397.2 (m+1).

EXAMPLE 36 R¹=(4-PhO)-Ph; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenoxyphenoxy)phenyl]-3-methylpyrrolidinecarboxylate

[0428] Cryptand Etherification Procedure

[0429] To a stirred suspension of sodium hydride (16 mg of a 60%dispersion in mineral oil, 0.40 mmol) in dry anisole (2 mL) was addedIntermediate 74 (100 mg, 0.32 mmol), portionwise, over 5 minutes with H₂evolution, at room temperature under a nitrogen atmosphere. Afterstirring for 30 minutes, tris[2-(2-methoxyethoxy)ethyl]amine (10 mL,0.03 mmol), copper (I) chloride (10 mg, 0.10 mmol), and 4-bromo-biphenylether were added, and the resulting mixture heated at reflux for 20hours. The anisole then was removed via vacuum distillation. The residuedissolved in EtOAc (25 mL), and filtered through GF/F filter paper. Thefiltrate was washed with 1N aq. HCl (20 mL), dried (Na₂SO₄), filtered,and concentrated in vacuo. The residue was purified via radialchromatography (2 mm silica plate with 1:1 hexanes:EtOAc) to provideExample 36 as a tan oil (40 mg, 26%).

[0430]¹H NMR (400 MHz, CDCl₃; mixture of rotomers) δ: 7.30 (dd, 2H),7.09-6.86 (m, 10H), 3.88-3.49 (m, 11H), 3.28 (d, 0.5H), 3.19 (d, 0.5H),1.93 (br s, 0.5H) 1.83 (br s, 0.5H), 1.12 (dd, 3H), 0.71 (br s, 3H).LRMS (Electrospray, positive): Da/e 478.2 (m+1).

EXAMPLE 37 R¹=(4-PhO)-Ph; R³=CO₂CH₃: Other Carbinol Diastereomer Methyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenoxyphenoxy)phenyl]-3-methylpyrrolidinecarboxylate

[0431] Prepared from the (1S)-carbinol isomer Intermediate 75 via thecryptand etherification procedure of Example 36.

[0432]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.32 (t, 2H), 7.07(dt, 1H), 7.03-6.74 (m, 9H), 3.91-3.55 (m, 9H), 3.35-3.17 (m, 3H), 2.16(d, 0.5H), 1.38 (br s, 0.5H), 1.12 (d, 3H), 0.85 (s, 3H). LRMS(Electrospray, positive): Da/e 478.2 (m+1).

EXAMPLE 38 R¹=(4-Ph)-Ph; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenylphenoxy)phenyl]-3-methylpyrrolidinecarboxylate

[0433] Prepared from Intermediate 74 via the cryptand etherificationprocedure of Example 36.

[0434]¹H NMR (400 MHz, CDCl₃; mixture of rotomers) δ: 7.55 (d, 2H), 7.51(d, 2H), 7.42 (t, 2H), 7.31 (t, 1H), 7.05 (dt, 1H), 6.98-6.92 (m, 4H),3.87-3.54 (m, 11H), 3.29 (d, 0.5H), 3.19 (d, 0.5H), 1.64 (br s, 0.5H),1.57 (br s, 0.5H), 1.14 (dd, 3H), 0.74 (s, 3H). LRMS (Electrospray,positive): Da/e 462.2 (m+1).

EXAMPLE 39 R¹=(4-Ph)-Ph; R³=CO₂CH₃: Other Carbinol Diastereomer Methyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenylphenoxy)phenyl]-3-methylpyrrolidinecarboxylate

[0435] Prepared from the (1S)-carbinol isomer Intermediate. 75 via thecryptand etherification procedure of EXAMPLE 36.

[0436]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.56 (d, 2H), 7.52(dt, 2H), 7.42 (t, 2H), 7.32 (t, 1H), 7.10-6.94 (m, 5H), 3.93-3.58 (m,9H), 3.38-3.18 (m, 3H), 1.13 (d, 3H), 0.88 (s, 3H) LRMS (Electrospray,positive): Da/e 462.2 (m+1).

EXAMPLE 40 R¹=Ph; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(4-methoxy-3-phenoxyphenyl)-3-methylpyrrolidinecarboxylate

[0437] Prepared from Intermediate 74 via the cryptand etherificationprocedure of Example 36.

[0438]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.32-7.26 (m, 3H),7.02 (t, 2H), 6.94-6.88 (m, 3H), 3.85-3.49 (m, 11H), 3.27 (d, 0.5H),3.18 (d, 0.5H), 1.12 (t, 3H), 0.71 (s, 3H). LRMS (Electrospray,positive): Da/e 386.3 (m+1).

EXAMPLE 41 R¹=Ph; R³=CO₂CH₃: Other Carbinol Diastereomer Methyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-(4-methoxy-3-phenoxyphenyl)-3-methylpyrrolidinecarboxylate

[0439] Prepared from the (1S)-carbinol isomer Intermediate 75 via thecryptand etherification procedure of Example 36.

[0440]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.29 (t, 2H),7.08-6.85 (m, 6H), 3.87-3.52 (m, 9H), 3.34-3.16 (m, 3H), 1.11 (d, 3H),0.85 (s, 3H). LRMS (Electrospray, positive): Da/e 386.3 (m+1).

EXAMPLE 42 R¹=4-fluorophenyl; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[3-(4-fluorophenoxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylate

[0441] Prepared from Intermediate 74 via the cryptand etherificationprocedure of Example 36.

[0442]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.05-6.84 (m, 7H),3.89-3.45 (m, 11H), 3.28 (d, 0.5H), 3.18 (d, 0.5H), 1.13 (t, 3H), 0.71(br s, 3H) LRMS (Electrospray, positive): Da/e 404.4 (m+1).

EXAMPLE 43 R¹=CH₂C₃H₅; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylate

[0443] K₂CO₃ Etherification Procedure

[0444] To a stirred mixture of Intermediate 74 (50 mg, 0.16 mmol) andpowdered K₂CO₃ (24.6 mg, 0.18 mmol) in dry DMF (1 mL) was addedbromomethylcyclopropane (16.5 μL, 0.17 mmol) via syringe at roomtemperature under a nitrogen atmosphere. The resulting mixture washeated at 65° C. for 24 hours, then allowed to cool to room temperature.The reaction then was diluted with water (5 mL) and extracted with Et₂O(3×20 mL). The combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified via radialchromatography (1 mm silica plate with 30% EtOAc in hexanes) to provideExample 43 as a clear oil (30 mg, 51%).

[0445]¹H NMR (400 MHz, CDCl₃; mixture of rotomers) δ: 6.84-6.75 (m, 3H),3.94-3.54 (m, 13H), 3.29 (d, 0.5H), 3.21 (d, 0.5H), 1.72 (br s, 0.5H),1.65 (br s, 0.5H), 1.30 (c, 1H), 1.13 (t, 3H), 0.73 (s, 3H), 0.61 (c,2H), 0.34 (c, 2H) LRMS (Electrospray, positive): Da/e 364.3 (m+1).

EXAMPLE 44 R¹=CH₂C₃H₅; R³=CO₂CH₃ Diastereomer Methyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylate

[0446] Prepared from (1S)-carbinol isomer Intermediate 75 via the K₂CO₃etherification procedure of Example 43 using bromomethylcyclopropane.

[0447]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.84-6.75 (m, 3H),3.89-3.58 (m, 11H), 3.33-3.20 (m, 3H), 1.52 (br s, 1H), 1.31 (c, 1H),1.11 (d, 3H) 0.89 (s, 3H), 0.62 (m, 2H), 0.33 (m, 2H) LRMS(Electrospray, positive): Da/e 364.3 (m+1).

EXAMPLE 45 R¹=2-thiazole; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(4-methoxy-3-(1,3-thiazol-2-yloxy)phenyl)-3-methylpyrrolidinecarboxylate

[0448] Prepared from Intermediate 74 via the K₂CO₃ etherificationprocedure of Example 43 using 2-bromothiazole.

[0449]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.24-7.12 (m, 3H),6.96 (d, 1H), 6.75 (d, 1H), 3.89-3.52 (m, 11H), 3.29 (d, 0.5H), 3.20 (d,0.5H), 1.74 (br s, 1H), 1.14 (t, 3H), 0.74 (s, 3H). LRMS (Electrospray,positive): Da/e 393.2 (m+1).

EXAMPLE 46 R¹=2-thiazole; R³=CO₂CH₃, Diastereomer Methyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-(4-methoxy-3-(1,3-thiazol-2-yloxy)phenyl)-3-methylpyrrolidinecarboxylate

[0450] Prepared from (1S)-carbino) isomers Intermediate 75 via the K₂CO₃etherification procedure of Example 43.

[0451]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.17 (d, 1H), 7.16(d, 1H), 7.11 (dd, 1H), 6.97 (d, 1H), 6.75 (d, 1H), 3.86-3.59 (m, 9H),3.42-3.19 (m, 3H), 1.52 (br s, 1H), 1.14 (d, 3H), 0.87 (s, 3H) LRMS(Electrospray, positive): Dale 393.2 (m+1).

EXAMPLE 47 R¹=2-(N-Methyl)benzimidazole; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-benzimidazol-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylate

[0452] Prepared from Intermediate 74 via the K₂CO₃ etherificationprocedure of Example 43 with 2-chloro-N-methylbenzimidazole.

[0453]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.50 (d, 1H),7.29-7.10 (m, 5H), 6.95 (d, 1H), 3.80-3.66 (m, 13H), 3.57 (t, 1H), 3.29(d, 0.5H) 3.20 (d, 0.5H), 2.04 (br s, 1H), 1.13 (t, 3H), 0.77 (s, 3H).LRMS (Electrospray, positive): Da/e 440.2 (m+1).

EXAMPLE 48 R¹=2-(N-Methyl)benzimidazole; R³=CO₂CH₃: Diastereomer Methyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-(3-benzimidazol-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylate

[0454] Prepared from the (1S)-carbinol isomer Intermediate 75 via theK₂CO₃ etherification procedure of Example 43 using2-chloro-1-methyl-1H-benzimidazole.

[0455]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.50 (d, 1H), 7.50(d, 1H), 7.30-7.09 (m, 5H), 6.96 (d, 1H), 3.87-3.63 (m, 12H), 3.40-3.21(m, 3H), 1.15 (d, 3H), 0.91 (s, 3H) LRMS (Electrospray, positive): Da/e440.2 (m+1).

EXAMPLE 49 R¹=CH₂CH₂CH₂Ph; R³=CO₂CH₃ Methyl 3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylpropoxy)phenyl]-3-methylpyrrolidinecarboxylate

[0456] Prepared from Intermediate 74 via the K₂CO₃ etherificationprocedure of Example 43 using 3-phenyl-propyl chloride.

[0457]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.35-7.17 (m, 5H),6.85-6.77 (m, 3H), 4.02 (dt, 2H), 3.90-3.52 (m, 11H), 3.30 (d, 0.5H),3.21 (d, 0.5H), 2.82 (t, 2H), 2.14 (p, 2H), 1.54 (br s, 0.5H), 1.49 (brs, 0.5H), 1.13 (t, 3H), 0.72 (s, 3H).

EXAMPLE 50 R¹=CH₂CH₂CH₂Ph; R³=CO₂CH₃, Other Carbinol Diastereomer Methyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylpropoxy)phenyl]-3-methylpyrrolidinecarboxylate

[0458] Prepared from the (1S)-carbinol isomer Intermediate 75 via theK₂CO₃ etherification procedure of Example 43 using the (1S)-carbinolisomer of Intermediate 75.

[0459]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.33-7.19 (m, 5H),6.84-6.78 (m, 2H), 6.72 (br s, 1H), 4.01 (t, 2H), 3.90-3.56 (m, 9H),3.34-3.23 (m, 3H), 2.82 (t, 2H), 2.15 (p, 2H), 1.11 (d, 3H), 0.89 (s,3H).

EXAMPLE 51 R¹=CH₂CH₂CH₂CH₂Ph; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenylbutoxy)phenyl]-3-methylpyrrolidinecaboxylate

[0460] Prepared from Intermediate 74 via the K₂CO₃ etherificaitonprocedure of Example 43 using 1-chloro-4-phenylbutane.

[0461]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.32-7.15 (m, 5H),6.84-6.74 (m, 3H), 4.00 (t, 2H), 3.89-3.51 (m, 11H), 3.30 (d, 0.5H),3.22 (d, 0.5H), 2.69 (t, 2H), 1.90-1.79 (m, 4H), 1.41 (dd, 1H), 1.13 (t,3H), 0.73 (s, 3H)

EXAMPLE 52 R¹=CH₂CH₂CH₂CH₂Ph; R³=CO₂CH₃, Other Carbinol DiastereomerMethyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenylbutoxy)phenyl]-3-methylpyrrolidinecarboxylate

[0462] Prepared from Intermediate 74 via the K₂CO₃ etherificationprocedure of Example 43 using 1-chloro-5-phenylpentane.

[0463]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.32-7.16 (m, 5H),6.83-6.70 (m, 3H), 3.99 (t, 2H), 3.90-3.58 (m, 9H), 3.34-3.21 (m, 3H),2.69 (t, 2H), 1.90-1.77 (m, 4H), 1.45 (br s, 1H), 1.12 (d, 3H), 0.90 (s,3H). LRMS (Electrospray, positive): Da/e 442.4 (m+1).

EXAMPLE 53 R¹=CH₂CH₂Ph; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(2-phenylethoxy)phenyl]-3-methylpyrrolidinecarboxylate

[0464] Prepared from Intermediate 74 via the K₂CO₃ etherificationprocedure of Example 43 using 2-phenethyl bromide.

[0465]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.39-7.23 (m, 5H),6.84-6.78 (m, 3H),4.20 (t, 2H), 3.87-3.52 (m, 11H), 3.30 (d, 0.5H), 3.21(d, 0.5H), 3.15 (t, 2H), 1.13 (t, 3H), 0.73 (s, 3H). LRMS (Electrospray,positive): Da/e 414.3 (m+1).

EXAMPLE 54 R¹=CH₂CH₂Ph; R³=CO₂CH₃, Other Carbinol Diastereomer Methyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(2-phenylethoxy)phenyl]-3-methylpyrrolidinecarboxylate

[0466] Prepared from the (1S)-carbinol isomer Intermediate 75 via theK₂CO₃ etherification procedure of Example 43.

[0467]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.34-7.24 (m, 5H),6.83 (d, 1H), 6.79 (dd, 1H), 6.73 (br s, 1H), 4.18 (t, 2H), 3.89-3.56(m, 9H), 3.31-3.20 (m, 3H), 3.15 (t, 2H), 1.11 (d, 3H), 0.89 (s, 3H).

EXAMPLE 55 R¹=C₅H₉; R³=CH₂-2-pyridyl(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-(2-pyridylmethyl)pyrrolidin-3-yl]ethan-1-ol

[0468] Reductive Amination Procedure

[0469] To a stirred solution of Intermediate 68 (32 mg, 0.1 mmol) andpyridine 2-carboxaldehyde (10 mL, 0.1 μmol) in dry 1,2-dichloroethane(0.3 mL) was added sodium triacetoxyborohydride (30 mg, 0.14 mmol) undera nitrogen atmosphere at room temperature. After stirring for 3 hours,the reaction was quenched with saturated aqueous NaHCO₃ (0.1 mL) andstirred for 5 minutes. The reaction was diluted with EtOAc (20 mL),washed with saturated aqueous NaHCO₃ (20 mL), and brine (20 mL), thendried (MgSO₄), filtered, and concentrated in vacuo to provide Example 55as a yellow oil (40.4 mg, 98%).

[0470]¹H NMR (400 MHz, CDCl₃) δ: 8.54 (ddd, 1H), 7.68 (dt, 1H), 7.43 (d,1H), 7.18 (ddd, 1H), 6.79-6.73 (m, 3H), 4.75 (c, 1H), 3.89-3.77 (m, 5H),3.69 (q, 1H), 3.59 (t, 1H), 3.33 (t, 1H), 3.16 (d, 1H), 2.70 (t, 1H),2.21 (d, 1H), 1.92-1.80 (m, 6H), 1.64-1.57 (m, 2H), 1.14 (d, 3H), 0.50,3H). LRMS (Electrospray, positive): Da/e 411.4 (m+1).

EXAMPLE 56 R¹=C₅H₉; R³=CH₂-3-pyridyl(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-(3-pyridylmethyl)pyrrolidin-3-yl]ethan-1-ol

[0471] Prepared from Intermediate 68 via the reductive aminationprocedure of Example 55 using pyridine-3-carboxaldehyde.

[0472]¹H NMR (400 MHz, CDCl₃) δ: 8.54 (d, 1H), 8.51 (dd, 1H), 7.68 (d,1H), 7.26 (dd, 1H), 6.78-6.71 (m, 3H), 4.74 (c, 1H), 3.86-3.78 (m, 4H),3.68 (q, 1H), 3.64 (d, 1H), 3.53 (t, 1H), 3.22 (t, 1H), 3.05 (d, 1H),2.62 (t, 1H), 2.14 (d, 1H), 1.92-1.78 (m, 6H), 1.64-1.56 (m, 2H), 1.12(d, 3H), 0.50 (s, 3H). LRMS (Electrospray, positive): Da/e 411.4 (m+1).

EXAMPLE 57 R¹=C₅H₉; R³=CH₂-4-pyridyl(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-(4-pyridylmethyl)pyrrolidin-3-yl]ethan-1-ol

[0473] Prepared from Intermediate 68 via the reductive aminationprocedure of Example 55 using pyridine-4-carboxaldehyde.

[0474]¹H NMR (400 MHz, CDCl₃) δ: 8.54 (d, 2H), 7.27 (d, 2H), 6.79-6.72(m, 3H), 4.74 (c, 1H), 3.86-3.74 (m, 4H), 3.70 (q, 1H), 3.64 (d, 1H),3.55 (t, 1H), 3.23 (t, 1H), 3.06 (d, 1H), 2.64 (t, 1H), 2.15 (d, 1H),1.92-1.80 (m, 6H), 1.65-1.58 (m, 2H), 1.14 (d, 3H), 0.52 (s, 3H). LRMS(Electrospray, positive): Da/e 411.4 (m+1).

EXAMPLE 58 R¹=C₅H₉; R³=CH₂CH₂CO₂CH₂Ph Phenylmethyl3-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]propanoate

[0475] To a stirred solution of benzyl acrylate (19.4 mg, 0.12 mmol) indry DMF (0.1 mL) was added Intermediate 68 (12.8 mg, 0.04 mmol) andpowdered K₂CO₃ (26.5 mg, 0.18 mmol) under a nitrogen atmosphere. Theresulting mixture was allowed to stir at 80° C. for 16 hours, thenallowed to cool to room temperature. The reaction was diluted withCH₂Cl₂ (20 mL), washed with water, saturated aqueous NaHCO₃, and brine,then dried (Na₂SO₄), filtered, and concentrated in vacuo. The residuewas purified via flash chromatography (2:1 EtOAc:hexanes on silica gel)to provide Example 58 (11.7 mg, 60%).

[0476]¹H NMR (400 MHz, CDCl₃) δ: 7.37-7.31 (m, 5H), 6.81-6.72 (m, 3H),5.14 (q, 2H), 4.76 (c, 1H), 3.87-3.81 (m, 4H),3.65 (q, 1H), 3.54 (t,1H), 3.31 (t, 1H), 3.15 (d, 1H), 2.82 (dt, 2H), 2.62-2.54 (m, 3H), 2.08(d, 1H), 1.91-1.81 (m, 6H), 1.66-1.56 (m, 2H), 1.15 (d, 3H), 0.48 (s,3H). LRMS (Electrospray, positive): Da/e 482.3 (m+1).

EXAMPLE 59 R¹=C₅H₉; R³=CH₂CH₂CO₂H3-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]propanoicacid

[0477] Prepared from Example 58 via the debenzylation procedure ofIntermediate 31.

[0478]¹H NMR (400 MHz, CDCl₃) δ: 6.82-6.71 (m, 3H), 4.80 (c, 1H),4.06-3.15 (m, 11H), 2.73 (br s, 2H), 1.91-1.74 (m, 6H), 1.63-1.53 (m,2H), 1.14 (d, 3H), 0.68 (s, 3H).

EXAMPLE 60 R¹=C₅H₉; R³=CH₂CO₂CH₂Ph Phenylmethyl2-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]acetate

[0479] Prepared from Intermediate 68 via the Hunig's base mediatedcoupling procedure of Intermediate 74 using benzyl bromoacetate.

[0480]¹H NMR (400 MHz, CDCl₃) δ: 7.41-7.32 (m, 5H), 6.82-6.73 (m, 3H),5.18 (q, 2H), 4.77 (c, 1H), 3.82 (s, 3H), 3.68 (q, 1H), 3.59 (t, 1H),3.52 (d, 1H), 3.36-3.30 (m, 2H), 3.24 (d, 1H), 2.88 (t, 1H), 2.31 (d,1H), 1.93-1.80 (m, 6H), 1.65-1.56 (m, 2H), 1.16 (d, 3H), 0.53 (s, 3H)LRMS (Electrospray, positive): Da/e 468.3 (m+1).

EXAMPLE 61 R¹=C₅H₉; R³=CH₂CO₂H2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]aceticacid

[0481] Prepared from Example 60 via debenzylation procedure ofIntermediate 31.

[0482]¹H NMR (400 MHz, CDCl₃) δ: 6.77-6.68 (m, 3H), 5.56 (br s, 1H),4.77 (c, 1H), 3.99-3.85 (m, 4H), 3.82-3.59 (m, 7H), 2.88 (br s, 1H),1.91-1.75 (m, 6H), 1.59-1.51 (m, 2H), 11.1 (d, 3H), 0.67 (s, 3H). LRMS(Electrospray, negative): Da/e 376.2 (m−1).

EXAMPLE 62 R¹=C₅H₉; R³=COCH(OAc)Ph2-[(3R)-3-((1R)-1-Hydroxyethyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-1-phenylethylacetate

[0483] Prepared from Intermediate 68 (104 mg, 0.33 mmol) and O-acetylmandelic acid chloride (75 μL, 0.33 mmol) by the acylation procedure ofExample 7 to give Example 62 (149 mg, 100%).

[0484] 1H-NMR (400 MHz, CDCl₃) δ: 7.60-7.37 (m, 5H), 6.82-6.70 (m, 3H),6.08 (m, 1H), 4.76 (m, 1H), 4.05-3.32 (m, 7H), 3.81 (s, 3H), 2.20 (s,3H), 1.95-1.53 (br m, 5H), 1.13 and 0.51 (doublets, 3H, rotomers), 0.79and 0.41 (singlets, 3H, rotomers).

EXAMPLE 63 R¹=C₅H₉; R³=COCH(OH)Ph1-[(3R)-3-((1R)-1-Hydroxyethyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxy-2-phenylethan-1-one

[0485] Prepared from Example 62 by the LiOH hydrolysis procedure ofIntermediate 5 to provide Example 63 as a white foam (99 mg, 66%).

[0486] 1H-NMR (400 MHz, CDCl₃) δ: 7.41-7.26 (m, 5H), 6.80-6.41 (m, 3H),5.16-5.07 (m, 1H), 4.75-4.54 (multiplets, 1H, rotomers anddiastereomers), 4.06-2.80 (m, 7H), 3.81 and 3.79 and 3.78 (singlets, 3H,rotomers and diastereomers), 1.95-1.55 (br m, 5H), 1.15 and 1.02(doublets, 3H, rotomers), 0.77 and 0.75 and 0.46 and 0.38 (singlets, 3H,rotomers and diastereomers). LRMS (Electrospray, positive): Da/e 454.5(m+1).

EXAMPLE 64 R¹=C₅H₉; R³=COCH₂OCH₂Ph1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(phenylmethoxy)ethan-1-one

[0487] Prepared from Intermediate 68 (176 mg, 0.574 mmol) by the Hunig'sbase procedure of Intermediate 74 using benzyloxyacetyl chloride (31 μL,0.22 mmol, 2 eq), yielding a clear, colorless oil (79 mg, 29%).

[0488]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.38-7.28 (m, 5H),6.77-6.73 (m, 3H), 4.73-4.71 (m, 1H), 4.65-4.64 (m, 2H), 4.14-3.19 (c,12H), 2.07-1.56 (m, 8H), 1.16-1.09 (dd, 3H), 0.72 (s, 3H).

EXAMPLE 65 R¹=C₅H₉; R³=COCH₂OH1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyethan-1-one

[0489] Prepared from Example 64 by the debenzylation procedure ofIntermediate 31 yielding a white solid (47 mg, 73%).

[0490]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.82-6.76 (m, 3H),4.75-4.73 (m, 1H), 4.15-3.04 (c, 12H), 1.92-1.61 (m, 9H), 1.27-1.24 (dd,3H), 0.76 (s, 3H). LRMS (Electrospray, positive): Da/e 378.2 (m+1).

EXAMPLE 66 R¹=C₅H₉; R³=(S)—COCH(OAc)CH₃2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-1-methyl-2-oxoethylacetate

[0491] Prepared from Intermediate 68 (106 mg, 0.330 mmol) by theacylation procedure of Example 7 using (S)-(−)-2-acetoxypropionylchloride (84 μL, 0.66 mmol, 2 eq), yielding a clear, colorless oil thatwas not purified further.

EXAMPLE 67 R¹=C₅H₉; R³=(S)—COCH(OH)CH₃1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-hydroxypropan-1-one

[0492] The crude compound of Example 66 was deprotected by the LiOHprocedure of Intermediate 5 to give Example 67 as a white solid (22 mg,17% for two steps).

[0493]¹H NMR (400 MHz, CDCl₃) δ: 6.82-6.76 (m, 3H), 4.75-4.73 (m, 1H),4.38-4.35 (m, 1H), 3.88-3.55 (c, 9H), 3.39-3.25 (dd, 1H), 1.92-1.58 (m,9H), 1.41-1.36 (dd, 3H), 1.18-1.14 (dd, 3H), 0.77-0.76 (d, 3H). LRMS(Electrospray, positive): Da/e 392.3 (m+1).

EXAMPLE 68 R¹=C₅H₉; R³=CO(CH₂CH₂)OAc{[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]carbonyl}-cyclopropylacetate

[0494] Intermediate 68 (97.6 mg, 0.306 mmol) was acylated by theacylation procedure of Example 7 using 2-acetoxy-2-cyclopropanethanoylchloride (99 mg, 0.61 mmol, 2 eq), yielding a clear, colorless oil (77mg, 56%).

[0495]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.78-6.71 (m, 3H),4.72-4.71 (m, 1H), 3.80-3.36 (c, 10H), 2.08 (s, 3H), 1.90-1.50 (m, 11H),1.16-1.11 (d, 3H), 0.96 (br s, 1H), 1.18-1.14 (dd, 3H), 0.70 (s, 3H).

EXAMPLE 69 R¹=C₅H₉; R³=CO(CH₂CH₂)OH3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinylhydroxycyclo-propyl ketone

[0496] The compound of Example 68 (77 mg) was hydrolyzed by the LiOHprocedure of Intermediate 5 to give Example 69 as a white solid (34 mg,44% for two steps).

[0497]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.80-6.75 (m, 3H),4.74-3.33 (c, 10H), 2.30 (br s, 1H), 1.93-1.56 (m, 8H), 1.37-0.89 (m,8H), 0.74-0.72 (d, 3H). LRMS (Electrospray, positive): Da/e 404.4 (m+1).

EXAMPLE 70 R¹=C₅H₉; R³=COCH(OAc)(CH₃)CH₃2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1,1-dimethyl-2-oxoethylacetate

[0498] Intermediate 68 (124 mg, 0.0.389 mmol) was acylated by theacylation procedure of Example 7 using (+)-2-acetoxy-2-methylpropionylchloride (11 μL, 0.78 mmol, 2 eq.). The resulting oil was not purifiedfurther.

EXAMPLE 71 R¹=C₅H₉; R³=COCH(OH)(CH₃)CH₃1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxy-2-methylpropan-1-one

[0499] The crude product of Example 70 was converted by the LiOHhydrolysis procedure of Intermediate 5 to the give Example 71 as a whitesolid (47 mg, 30%).

[0500]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.79-6.75 (m, 3H),4.75 (br s, 1H), 4.49 (br s, 1H), 3.91-3.48 (c, 10H), 1.90-1.46 (m,14H), 1.18-1.14 (dd, 3H), 0.77-0.74 (d, 3H). LRMS (Electrospray,positive): Da/e 406.3 (m+1).

EXAMPLE 72 R¹=C₅H₉; R³=COCO₂CH₃ Methyl2-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoacetate

[0501] Intermediate 68 (57.5 mg, 0.180 mmol) was converted by the DIEAprocedure of Intermediate 32 using methyl oxalyl chloride to yieldExample 72 as a clear, colorless oil (26.8 mg, 36%).

[0502]¹H NMR (400 MHz, CDCl₃) δ: 6.81-6.77 (m, 3H), 4.75-4.74 (m, 1H),4.12-3.45 (c, 13H), 1.91-1.52 (m, 8H), 1.18-1.13 (dd, 3H), 0.78-0.75 (d,3H). LRMS (Electrospray, positive): Da/e 406.4 (m+1).

EXAMPLE 73 R¹=C₅H₉; R³=COCO₂H2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoaceticacid

[0503] Example 72 (46.8 mg, 0.116 mmol) was converted by the LiOHprocedure of Intermediate 5 to give Example 73 as a clear, colorlessfilm (34 mg, 76%).

[0504]¹H NMR (400 MHz, CDCl₃) δ: 6.82-6.76 (m, 3H), 4.75-4.73 (m, 1H),4.43-3.49 (c, 10H), 1.92-1.58 (m, 8H), 1.19-1.16 (dd, 3H), 0.78-0.76 (d,3H). LRMS (Electrospray, negative): Da/e 390.2 (m−1).

EXAMPLE 74 R¹=C₅H₉; R³=COCONH₂2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-acetamide

[0505] Example 72 (7.1 mg, 0.014 mmol) was dissolved in THF (0.5 mL),NH₄OH (0.5 mL) was added, and the apparatus was sealed and stirred for 2hours at room temperature. TLC (1:1 EtOAc:hexanes) showed completeconsumption of starting material. The reaction was diluted with EtOAc(20 mL), and the organic layers were washed with brine (2×15 mL). Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to give aclear, colorless oil (6.6 mg, 117%).

[0506]¹H NMR (400 MHz, CDCl₃) δ: 7.36 (br s, 1H), 6.82-6.79 (m, 3H),5.53 (br s, 1H), 4.76-4.75 (m, 1H), 4.44-3.47 (c, 10H), 1.92-1.58 (m,8H), 1.18-1.17 (d, 3H), 0.78-0.74 (d, 3H). LRMS (Electrospray,negative): Da/e 389.1 (m−1).

EXAMPLE 75 R¹=PhC≡CCH₂; R³=COCONH₂2-{(3S,4S)-3-((R)-1-Hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)-phenyl]-3-methylpyrrolidin-1-yl}-2-oxo-acetamide

[0507] Prepared by acylation of Intermediate 73 with methyl oxalylchloride by the DIEA procedure of Intermediate 32, removal of thet-butyl group by the procedure of Intermediate 72, O-alkylation withIntermediate 90 by the K₂CO₃ etherification procedure of Example 43, andamidation by the procedure of Example 74.

[0508]¹H NMR data δ: 7.28-7.42 (m, 5H); 7.08 (sd, 1H); 6.83-6.87 (m,2H); 5.45 (bs, 1H); 5.0 (s, 2H); 4.42-4.48 (2d, 0.5H); 4.26 (t, 0.5H);3.72-4.01 (m, 3.5H); 3.89 (s, 3H); 3.50-3.70 (m, 1H); 3.44 (d, 0.5H);0.96-0.99 (dd, 3H); 0.71 (d, 3H).

EXAMPLE 76 R¹=4-CF₃PhC≡CCH₂; R³=COCONH₂2-((3S,4S)-3-((R)-1-Hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoromethyl-phenyl)prop-2-ynyloxy]-phenyl}-3-methylpyrrolidin-1-yl)-2-oxo-acetamide

[0509] Prepared as described in Example 75, using Intermediate 92 as theO-alkylating reagent.

[0510]¹H NMR data δ: 7.50-7.61 (m, 4H); 7.04 (s, 1H); 6.85-6.91 (m, 2H);5.69 (bs, 1H); 5.00 (s, 2H); 4.42-4.49 (2d, 0.5H); 4.26 (t, 0.5H);3.69-4.07 (m, 5H); 3.90 (s, 3H); 3.45-3.58 (m, 1H); 1.04-1.07 (dd, 3H);0.73 (d, 3H)

EXAMPLE 77 R¹=4-FPhOCH₂CH₂CH₂; R³=COCONH₂2-[(3S,4S)-4-{3-[3-(4-Fluorophenoxy)propoxy]-4-methoxyphenyl}-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-oxo-acetamide

[0511] Prepared as described in Example 75, using1-(3-chloropropoxy)-4-fluorobenzene as the alkylating reagent.

[0512]¹H NMR data δ: 6.93-6.99 (m, 2H); 6.82-6.88 (m, 5); 5.44 (s, 1H);4.40 (dd, 0.5H); 4.14-4.22(m, 5H); 3.83 (s, 3H); 3.69-4.04 (m, 5H); 3.56(d, 0.5H); 2.28 (quint, 2H); 1.16 (dd, 3H): 0.75 (d, 3H).

EXAMPLE 78 R¹=CH₂C₃H₅; R³=COCONH₂2-[(3S,4S)-4-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-oxo-acetamide

[0513] Prepared as described in Example 75, using cyclopropylmethylbromide as the alkylating reagent.

[0514]¹H NMR data δ: 6.80-6.81 (m, 3H); 5.50 (bs, 1H); 4.40 (2d, 0.5H);4.23 (t, 0.5H); 3.68-4.05 (m, 7H); 3.84 (s, 3H); 1.40 (t, 1H); 1.17 (sd,3H); 0.76 (d, 3H); 0.61-0.67 (m, 2H); 0.33-0.38 (m, 2H).

EXAMPLE 79 R¹=2-indanyl; R³=COCONH₂2-{(3S,4S)-3-((R)-1-Hydroxyethyl)-4-[3-(indan-2-yloxy)-4-methoxyphenyl]-3-methylpyrrolidin-1-yl}-2-oxo-acetamide

[0515] Prepared as described in Example 75, using 2-bromoindane as thealkylating reagent.

[0516]¹H NMR data δ: 7.16-7.24 (m, 4H); 6.84-6.87 (m, 3H); 5.51 (s, 1H);5.17-5.20 (m, 1H); 4.42-4.5 (2d, 0.5H); 4.24 (t, 0.5H); 3.60-4.06 (m,6H); 3.81 (s, 3H); 3.20-3.40 (m, 4H); 1.20 (sd, 3H); 0.78 (d, 3H).

EXAMPLE 80 R¹=C₅H₉; R³=COCONHCH₃2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-N-methyl-2-oxoacetamide

[0517] Example 72 (17.3 mg, 0.0427 mmol) was dissolved in THF (0.8 mL).Methylamine (40% in water, 0.5 mL) was added, and the apparatus wassealed and stirred for 1 hour at room temperature. TLC (3:1EtOAc:hexanes) showed complete consumption of starting material. Thereaction was diluted with EtOAc (20 mL), and the organic layers werewashed with brine (2×15 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to give a clear, colorless oil (16.9 mg, 97%).

[0518]¹H NMR (400 MHz, CDCl₃) δ: 7.59 (br s, 1H), 6.80-6.79 (m, 3H),4.75-4.73 (m, 1H), 4.47-3.46 (c, 10H), 2.89-2.87 (dd, 3H), 1.91-1.57 (m,8H), 1.18-1.16 (dd, 3H), 0.76-0.73 (d, 3H). LRMS (Electrospray,positive): Da/e 405.1 (m+1).

EXAMPLE 81 R¹=C₅H₉; R³=COCO-piperidine1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-piperidylethane-1,2-dione

[0519] Example 72 (25.4 mg, 0.0626 mmol) was dissolved in THF (0.8 mL).Piperidine (213 μL, 2.15 mmol, 34 eq.) was added, and the apparatus wassealed and heated at 53° C. for 12 hours. TLC (100% EtOAc) showed asmall amount of product formation. The reaction was diluted with EtOAc(20 mL), the organic layers were washed with 2N HCl (2×15 mL), 1N NaOH(15 mL), and brine (2×15 mL). The organic layer was dried over Na₂SO₄and concentrated in vacuo to give a clear, colorless oil (1.2 mg, 4%).

[0520]¹H NMR (400 MHz, CDCl₃) δ: 6.82-6.76 (m, 3H), 4.75 (m, 1H),4.01-3.27 (c, 14H), 1.89-1.59 (m, 14H), 1.18-1.13 (dd, 3H), 0.78-0.74(d, 3H).

EXAMPLE 82 R¹=C₅H₉; R³=COCONHC₅H₉2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-N-cyclopentyl-2-oxoacetamide

[0521] Example 72 (20.9 mg, 0.0515 mmol) was dissolved in THF (0.8 mL).Cyclopentylamine (211 μL, 2.13 mmol, 41 eq.) was added, and the reactionwas stirred at room temperature for 42 hours. The reaction was dilutedwith EtOAc (20 mL), and the organic layers were washed with 2N HCl (2×15mL), 1N NaOH (15 mL), and brine (2×15 mL). The organic layer was driedover Na₂SO₄ and concentrated in vacuo. The resulting oil was purified bysilica chromatography (100% EtOAc) to give a clear, colorless oil (14.0mg, 59%).

[0522]¹H NMR (400 MHz, CDCl₃) δ: 7.57-7.53 (br s, 1H), 6.8-6.78 (m, 3H),4.76-4.73 (br s, 1H), 4.48-3.44 (c, 9H), 2.04-1.48 (m, 18H), 1.18-1.16(d, 3H), 0.77-0.73 (d, 3H). LRMS (Electrospray, negative): Da/e 457.2(m−1).

EXAMPLE 83 R¹=C₅H₉; R³=COCONHCH₂Ph2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-N-benzylacetamide

[0523] Example 83 was prepared by the method of Example 82 usingbenzylamine to give a clear, colorless oil (9.4 mg, 47%).

[0524]¹H NMR (400 MHz, CDCl₃) δ: 7.96-7.92 (br s, 1H), 7.36-7.25 (m,3H), 4.75 (br s, 1H), 4.49-4.47 (d, 2H), 4.28-3.46 (c, 9H), 1.93-1.61(m, 8H), 1.19-1.16 (dd, 3H), 0.78-0.74 (d, 3H). LRMS (Electrospray,positive): Da/e 481.4 (m+1).

EXAMPLE 84 R¹=C₅H₉; R³=(R)—COCH(C₄H₉)NHCO₂CH₂PhN-{(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-butyl-2-oxoethyl}(phenylmethoxy)carboxamide

[0525] Intermediate 68 (39.5 mg, 0.129 mmol) was converted by the DIEAprocedure of Intermediate 32 to yield a clear, colorless oil (59.0 mg,80%).

[0526]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.36-7.26(m, 5H),6.82-6.71 (m, 3H), 5.71-5.68 (dd, 1H), 5.12-5.06 (m, 2H), 4.73 (m, 1H),4.49-4.47 (m, 1H), 4.12-2.58 (c, 8H), 2.03-1.25 (m, 16H), 1.16-1.14 (dd,3H), 0.92-0.84 (m, 3H), 0.73-0.72 (d, 3H).

EXAMPLE 85 R¹=C₅H₉; R³=(R)—COCH(NH₂)C₄H₉ (2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-aminohexan-1-one

[0527] Example 84 (59 mg, 0.10 mmol) was converted by the debenzylationprocedure of Intermediate 31 to give Example 85 as a white powder (43mg, 95%).

[0528]¹H NMR (CD₃OD, 400 MHz, mixture of rotomers) δ: 6.90-6.83 (m, 3H),3.85-3.30 (c, 10H), 2.00-1.37 (m, 14H), 1.14-1.11 (dd, 3H), 1.10-0.92(dt, 3H), 0.77 (s, 3H). LRMS (Electrospray, positive): Da/e 433.5 (m+1).

EXAMPLE 86 R¹=C₅H₉; R³=(R)—COCH(i-Pr)NHCO₂CH₂PhN-{(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-(methylethyl)-2-oxoethyl}(phenylmethoxy)-carboxamide

[0529] Intermediate 68 (43.7 mg, 0.143 mmol) was acylated by the Hunig'sbase method of Intermediate 74 using Z-D-Val-OSu (54.6 mg, 0.15 mmol,1.1 eq), yielding a clear, colorless oil (38.9 mg, 49%).

[0530]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.36-7.33 (m, 5H),6.80-6.71 (m, 3H), 5.62-5.59 (d, 1H), 5.10-5.06 (m, 2H), 5.84-5.72 (m,1H), 4.12-2.68 (c, 10H), 2.03-1.52 (m, 9H), 1.18-1.14 (dd, 3H),1.04-0.92 (m, 7H), 0.73-0.70 (d, 3H).

EXAMPLE 87 R¹=C₅H₉; R³=(R)—COCH(i-Pr)NH₂(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-amino-3-methylbutan-1-one

[0531] Example 86 (38.9 mg, 0.070 mmol) was converted by thedebenzylation procedure of Intermediate 31 to give Example 87 as clearsolid (26 mg, 88%).

[0532]¹H NMR (400 MHz, CDCl₃) δ: 6.42-6.33 (m, 3H), 4.36 (m, 1H),3.62-2.80 (c, 10H), 2.81-2.68 (m, 1H), 1.42-1.08 (m, 9H), 0.78-0.65 (m,9H), 0.24 (s, 3H). LRMS (Electrospray, positive): Da/e 419.5 (m+1).

EXAMPLE 88 R¹=C₅H₉; R³=(S)—COCH(OAc)C₆H₁₁2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-1-cyclohexyl-2-oxoethylacetate

[0533] Intermediate 68 (41.2 mg, 0.129 mmol) was acylated by the Hunig'sbase procedure of Intermediate 74 using (S)-(+)-acetoxyhexahydromandelicacid chloride (625 μL, 0.4121 M in CH₂Cl₂, 2 eq) to give Example 88 as aclear, colorless oil (40.5 mg, 63%).

[0534]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.78-6.77 (m, 3H),4.84-4.72 (m, 2H), 4.12-3.11 (m, 9H), 2.10 (d, 3H), 2.02-1.68 (m, 15H),1.38-0.99 (m, 10H), 0.81-0.74 (d, 3H).

EXAMPLE 89 R¹=C₅H₉; R³=(S)—COCH(OH)C₆H₁₁1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-cyclohexyl-2-hydroxyethan-1-one

[0535] Example 88 (40.5 mg, 0.0807 mmol) was converted by the LiOHhydrolysis procedure of Intermediate 5 to afford Example 89 as a clear,colorless oil (26.9 mg, 72%).

[0536]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.80-6.78(m, 3H),4.73 (m, 1H), 4.14-4.06 (m, 1H), 3.83-2.99 (c, 9H), 1.91-1.36 (m, 17H),1.35-1.11 (m, 7H), 0.79-0.78 (d, 3H). LRMS (Electrospray, positive):Da/e 460.3 (m+1).

EXAMPLE 90 R¹=C₅H₉; R³=(R)—COCH(OAc)C₆H₁₁1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2R)-2-cyclohexyl-2-acetoxyethan-1-one

[0537] Intermediate 68 (43.1 mg, 0.135 mmol) was converted by theHunig's base procedure of Intermediate 74 using(R)-(−)-acetoxyhexahydromandelic acid chloride (368 μL, 0.734 M inCH₂Cl₂, 2 eq) to give a clear, colorless oil (59.9 mg, 88%).

[0538]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.84-6.64(m, 3H),4.78-4.76 (m, 2H), 4.12-2.65 (c, 9H), 2.11 (d, 3H), 2.10-1.51 (m, 15H),1.38-0.98 (m, 10H), 0.73-0.65 (d, 3H).

EXAMPLE 91 R¹=C₅H₉; R³=(R)—COCH(OH)C₆H₁₁(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-cyclohexyl-2-hydroxyethan-1-one

[0539] Example 90 (59.9 mg, 0.119 mmol) was converted by the LiOHhydrolysis procedure of Intermediate 5 to give a clear, colorless film(46.6 mg, 84%).

[0540]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.85-6.74 (m, 3H),4.79-4.72 (m, 1H), 4.13-4.07 (m, 1H), 3.87-3.01 (c, 9H), 1.96-1.34 (m,17H), 1.34-1.08 (m, 7H), 0.78-0.77 (d, 3H). LRMS (Electrospray,positive): Da/e 460.4 (m+1).

EXAMPLE 92 R¹=C₅H₉; R³=(S)—COCH(C₄H₉)NHCO₂CH₂PhN-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-(1S)-1-butyl-2-oxoethyl}(phenylmethoxy)carboxamide

[0541] Intermediate 68 (40.6 mg, 0.125 mmol) was converted by theHunig's base procedure of Intermediate 74 using Z-L-Nle-ONp (53 mg, 0.15mmol, 1.1 eq) to give Example 92 as a clear, colorless oil (50.4 mg,71%).

[0542]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.36-7.25 (m, 5H),6.80-6.75 (m, 3H), 5.74-5.72 (dd, 1H), 5.10-5.06 (m, 2H), 4.74-4.53 (m,1H), 4.13 (m, 1H), 4.13-3.35 (c, 8H), 1.95-1.24 (m, 16H), 1.14-1.13 (d,3H), 0.93-0.87 (m, 3H), 0.74 (s, 3H).

EXAMPLE 93 R¹=C₅H₉; R³=(S)—COCH(C₄H₉)NH₂1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-aminohexan-1-one

[0543] Example 92 (50.4 mg, 0.0889 mmol) was subjected to thedebenzylation procedure of Intermediate 31 to give Example 93 as a whitesolid (31.7 mg, 82%).

[0544]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.89-6.74 (m, 3H),4.83-4.75 (m, 1H), 4.40-3.32 (c, 10H), 1.99-1.68 (m, 14H), 1.14-1.12 (m,3H), 1.04-0.95 (d, 3H), 0.91-0.88 (d, 3H). LRMS (Electrospray,positive): Da/e 433.5 (m+1).

EXAMPLE 94 R¹=C₅H₉; R³=(R)—COCH(OAc)(CH₂)₃CH₃(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-butyl-2-oxoethylacetate

[0545] Prepared from Intermediate 68 via the Hunig's base couplingprocedure of Intermediate 74 using (1R)-1-(chlorocarbonyl)pentylacetate.

[0546]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.81 (m, 2H),6.79-6.69 (m, 3H), 5.10-5.02 (m, 1H), 4.79-4.73 (m, 1H), 4.14-3.18 (c,9H), 2.14 (d, 3H), 1.94-1.76 (m, 8H), 1.53-1.34 (m, 4H), 1.20 (dd, 2H),0.96-0.86 (m, 3H), 0.74 (d, 3H).

EXAMPLE 95 R¹=C₅H₉; R³=(R)—COCH(OH)(CH₂)₃CH₃(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyhexan-1-one

[0547] Example 94 (5 mg, 0.011 mmol) was hydrolyed by LiOH to yieldExample 95 (2.5 mg, 55%), as a clear film.

[0548]¹H NMR (Methanol-d₄, 400 MHz) δ: 6.91-6.80 (m, 3H), 4.34-4.28 (m,1H), 4.04-3.35 (c, 9H), 1.90-1.77 (m, 8H), 1.74-1.62 (m, 2H), 1.55-1.23(m, 4H), 1.12 (d, 3H), 0.97-0.87 (m, 3H), 0.74 (s, 3H). LRMS(Electrospray, positive): Da/e 434.2 (m+1).

EXAMPLE 96 R¹=C₅H₉; R³=(S)—COCH(NHCBZ)CH₂PhN-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-(1S)-2-oxo-1-benzylethyl}(phenylmethoxy)carboxamide

[0549] Prepared from Intermediate 68 via the Hunig's base acylationprocedure of Intermediate 74 using the p-nitrophenylester ofN-CBZ-(S)-phenylalanine.

[0550]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.41-7.26 (m,10H), 6.78-6.42 (m, 3H), 5.78-5.74 (m, 1H), 5.14-5.05 (m, 2H), 4.76-4.70(m, 2H), 3.81 (s, 3H), 3.75-2.66 (c, 10H), 1.94-1.80 (m, 6H), 1.65-1.57(m, 2H), 1.08-0.99 (dd, 3H), 0.64 and 0.33 (s, 3H). LRMS (Electrospray,positive): Da/e 601.2 (m+1).

EXAMPLE 97 R¹=C₅H₉; R³=(S)—COCH(NH₂)CH₂Ph1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-amino-3-phenylpropan-1-one

[0551] Prepared from Example 96 via the debenzylation procedure ofIntermediate 31.

[0552]¹H NMR (Methanol-d₄, 400 MHz, mixture of rotomers) δ: 7.47-7.31(m, 5H), 6.88-6.47 (m, 3H), 4.78-4.76 (m, 1H), 4.48-4.44 (m, 1H),3.80-3.06 (c, 13H), 1.88-1.80 (m, 6H), 1.67-1.64 (m, 2H), 1.02 (d, 3H),0.75 and 0.34 (s, 3H). LRMS (Electrospray, positive): Da/e 467.5 (m+1).

EXAMPLE 98 R¹=C₅H₉; R³=(R)—COCH(NHCBZ)CH₂PhN-{(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-1-benzylethyl}(phenylmethoxy)carboxamide

[0553] Prepared from Intermediate 68 via the Hunig's base acylationprocedure of Intermediate 74 using the p-nitrophenylester ofN-CBZ-(R)-phenylalanine.

[0554]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.41-7.19 (m,10H), 6.77-6.46 (m, 3H), 5.70 (d, 1H), 5.14-5.04 (m, 2H), 4.76-4.69 (m,2H), 3.82 (s, 3H), 3.93-2.99 (c, 6H), 2,53 (d, 1H), 1.93-1.81 (m, 6H),1.62-1.56 (m, 2H), 1.06 (dd, 3H), 0.67 and 0.28 (s, 3H). LRMS(Electrospray, positive): Da/e 602.3 (m+1).

EXAMPLE 99 R¹=C₅H₉; R³=(R)—COCH(NH₂)CH₂Ph(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-amino-3-phenylpropan-1-one

[0555] Prepared from Example 98 via the debenzylation procedure ofIntermediate 31.

[0556]¹H NMR (Methanol-d₄, 400 MHz, mixture of rotomers) δ: 7.42-7.26(m, 5H), 6.88-6.65 (m, 3H), 4.80-4.78 (m, 1H), 4.42-4.39 (m, 1H),3.89-2.42 (c, 13H), 1.89-1.79 (m, 6H), 1.64-1.62 (m, 2H), 0.99 (dd, 3H),0.69 and 0.21 (s, 3H). LRMS (Electrospray, positive): Da/e 467.0 (m+1).

EXAMPLE 100 R¹=CH₂C₃H₅; R³=COCH(OAc)C₄H₉2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxo-1-propylethylacetate

[0557] Intermediate 67 (46 mg, 0.15 mmol) was converted by the Hunig'sbase procedure of Intermediate 74 using (±)-2-acetoxypropionyl chloride(29 mg, 0.165 mmol) to afford Example 100 (36 mg, 54%).

[0558] 1H-NMR (400 MHz, CDCl₃) δ: 6.86-6.69 (m, 3H), 5.30-5.02 (m, 1H),4.17-4.00 (m, 1H), 3.82 (s, 3H), 3.82-3.18 (m, 5H), 3.08 and 2.97(singlets, 2H, rotomers), 2.13 and 2.11 (singlets, 3H, rotomers),1.95-1.23 (m, 5H), 1.20-1.14 (m, 2H), 1.00-0.92 (m, 3H), 0.76 and 0.72(doublets, 3H, rotomers), 0.62 (m, 2H), 0.36 (m, 2H)

EXAMPLE 101 R¹=CH₂C₃H₅; R³=COCH(OH)C₄H₉1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxypentan-1-one

[0559] Example 100 (36 mg, 80 μmol) was subjected to the LiOH hydrolysisprocedure of Intermediate 5 to provide Example 101 as a clear film (30mg, 90%).

[0560]¹H-NMR (400 MHz, CDCl₃) δ: 6.85-6.73 (m, 3H), 4.23 (m, 1H),4.07-2.98 (m, 6H), 3.83 (s, 3H), 1.71-1.23 (m, 5H), 1.16 (m, 3H), 0.96(m, 3H), 0.77 (s, 3H), 0.62 (m, 2H), 0.37 (m, 2H). LRMS (Electrospray,positive): Da/e 406.5 (m+1).

EXAMPLE 102 R¹=CH₂C₃H₅; R³=(S)—COC(CH₃)OCH₂Ph1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-(phenylmethoxy)propan-1-one

[0561] Intermediate 67 (46 mg, 0.15 mmol) was converted by the Hunig'sbase procedure of Intermediate 74 using (2S)-2-(phenylmethoxy)propanoylchloride (59 mg, 0.3 mmol) to give Example 102 (54 mg, 77%).

[0562]¹H-NMR (400 MHz, CDCl₃) δ: 7.40-7.25 (m, 5H), 6.82-6.77 (m, 2H),6.72 (s, 1H), 4.63 (dd, 1H), 4.49 (dd, 1H), 4.22 (m, 1H), 3.98-3.38 (m,8H), 3.82 (s, 3H), 3.07 and 2.96 (singlets, 1H, rotomers), 1.43 (m, 3H),1.31 (m, 1H), 1.17 and 1.10 (doublets, 3H, rotomers), 0.72 and 0.70(singlets, 3H, rotomers), 0.62 (m, 2H), 0.37 (m, 2H).

EXAMPLE 103 R¹=CH₂C₃H₅; R³=(S)—COC(CH₃)OH1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-(hydroxy)propan-1-one

[0563] Prepared from Example 102 (54 mg, 0.12 mmol) by the debenzylationprocedure of Intermediate 31 to give Example 103 as a clear oil (45 mg,100%).

[0564] 1H-NMR (400 MHz, CDCl₃) δ: 6.84-6.73 (m, 3H), 4.44 (m, 1H),4.06-3.16 (m, 8H), 3.82 (s, 3H), 2.99 (d, 1H), 1.38 (m, 3H, rotomers),1.30 (m, 1H), 1.18 (m, 3H, rotomers), 0.78 and 0.76 (singlets, 3H,rotomers), 0.62 (m, 2H), 0.36 (m, 2H). LRMS (Electrospray, positive):Da/e 378.7 (m+1).

EXAMPLE 104 R¹=CH₂C₃H₅; R³=(R)—COCH (t-Bu) NHCO₂t-BuN-((1R)-2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-1S(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-(tert-butyl)-2-oxoethyl)(tert-butoxy)carboxamide

[0565] Intermediate 67 (46 mg, 0.15 mmol) was converted by the EDCIcoupling procedure of Example 27 using Boc-D-t-butylglycine (35 mg, 0.15mmol) to provide Example 104 as a white foam (62 mg, 80%).

[0566] 1H-NMR (400 MHz, CDCl₃) δ: 6.85-6.79 (m, 2H), 6.72-6.64 (m, 1H),4.36-4.00 (m, 3H, rotomers), 3.83 (s, 3H), 3.79 (d, 2H), 3.67-3.12 (m,4H, rotomers), 1.44 and 1.41 (singlets, 9H, rotomers), 1.32 (m, 1H),1.22-1.16 (m, 3H), 1.06 and 1.01 (singlets, 9H, rotomers), 1.02 (m, 3H),0.73 and 0.63 (singlets, 3H, rotomers), 0.61 (m, 2H), 0.36 (m, 2H).

EXAMPLE 105 R¹=CH₂C₃H₅; R³=(R)—COCH(t-Bu)NH₂(2R)-1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-3,3-dimethylbutan-1-one

[0567] To a stirred solution of Example 104 (62 mg, 0.12 mmol) in CH₂Cl₂(1.5 mL) at room temperature in a capped flask was added trifluoroaceticacid (77 μL, 1 mmol). After stirring overnight, the reaction wasconcentrated in vacuo to provide a crude product that appeared tocontain trifluoroacetate ester impurity. The crude product was dissolvedin 3:2 THF:H₂O (1.5 mL) at room temperature, and stirred in a cappedflask and treated with LiOH monohydrate (42 mg, 1 mmol). After 1 hour,the mixture was partitioned between EtOAc (15 mL) and water (15 mL). Theorganic layers were isolated, dried (MgSO₄), filtered, and concentratedin vacuo to provide Example 105 as a white foam (35 mg, 70%).

[0568] 1H-NMR (400 MHz, CDCl₃) δ: 6.85-6.82 (m, 2H), 6.78-6.73 (m, 1H),4.01-3.30 (m, 9H), 3.83 (s, 3H), 1.18 and 1.12 (doublets, 3H, rotomers),1.06 and 1.02 (singlets, 9H, rotomers), 0.78 and 0.68 (singlets, 3H,rotomers), 0.063 (m, 2H), 0.37 (m, 2H). LRMS (Electrospray, positive):Da/e 419.4 (m+1).

EXAMPLE 106 R¹=H; R³=(R)—COCH(CH₂OCH₂Ph)NHCO₂t-BuN-{2-[(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1R)-2-oxo-1-[(phenylmethoxy)methyl]ethyl}(tert-butoxy)carboxamide

[0569] To a stirred solution of N-Boc-O-benzyl-D-serine (2.95 gm, 10mmol) in THF (50 mL) at −78° C. under a nitrogen blanket was addedN-methyl morpholine (3.3 mL, 30 mmol) followed by isobutyl chloroformate(1.3 mL, 10 mmol). After stirring for 30 minutes, a solution/suspensionof Intermediate 70 (2.51 gm, 10 mmol) in THF (50 mL) was added bycannula. The reaction was stirred for 2 hours at −78° C., then warmed to0° C. for 2 hours. The reaction then was partially concentrated byrotary evaporator to approximately 25 mL, and partitioned between EtOAc(250 mL) and 2N HCl (250 mL). The organic layers were washed with 2N HCl(2×250 mL), saturated NaHCO₃ (3×250 mL), and saturated NaCl (1×250 mL).The organic layers were dried (MgSO₄), filtered, and concentrated invacuo to provide Example 106 as a yellow oil (4.2 gm, 79%).

[0570] 1H-NMR (400 MHz, CDCl₃) δ: 7.36-7.21 (m, 5H), 6.81-6.63 (m, 3H),5.81 (br s, 1H), 5.47 (m, 1H), 4.73 (m, 1H), 4.51 (m, 2H), 4.00-3.40 (m,83.83H), 3.84 and 3.82 (singlets, 3H, rotomers), 1.43 and 1.41(singlets, 9H, rotomers), 1.13 and 1.06 (doublets, 3H, rotomers), 0.95(m, 1H), 0.73 and 0.045 (singlets, 3H, rotomers).

EXAMPLE 107 R¹=CH₂C₃H₅; R³=(R)—COCH(CH₂OCH₂Ph)NHCO₂t-BuN-(2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-2-oxo-1-[(phenylmethoxy)methyl]ethyl)-(tert-butoxy)carboxamide

[0571] To a stirred solution of Example 106 (4.2 gm, 7.9 mmol) in DMF(24 mL) at room temperature under a nitrogen blanket was added powderedK₂CO₃ (5.45 gm, 39.5 mmol) followed by bromomethylcyclopropane (1.53 mL,15.8 mmol). The suspension was warmed to 65° C. for 4 hours, thentreated with more bromomethylcyclopropane (1.53 mL, 15.8 mmol). Thereaction was stirred another 16 hours at 65° C., then cooled to roomtemperature and partitioned between EtOAc (500 mL) and water (500 mL).The organic layers were washed with water (3×500 mL) and saturated NaCl(1×500 mL), dried (MgSO₄), filtered, and concentrated in vacuo. Thecrude product was divided into two batches, and chromatographed on aBiotage 40M column with 1/1 EtOAc/hexane to provide, after pooling andconcentration in vacuo of product containing fractions, Example 107(2.11 gm, 46%). A high R_(f) dialkylated product was identified as amajor impurity.

[0572] 1H-NMR (400 MHz, CDCl₃) δ: 7.36-7.22 (m, 5H), 6.81-6.71 (m, 3H),5.42 (m, 1H), 4.73 (m, 1H), 4.51 (m, 2H), 4.04-3.44 (m, 10H), 3.83 and3.81 (singlets, 3H, rotomers), 1.42 and 1.43 (singlets, 9H, rotomers),1.32 (m, 1H), 1.16 and 1.06 (doublets, 3H, rotomers), 0.76 and 0.45(singlets, 3H, rotomers), 0.62 (m, 2H), 0.37 (m, 2H).

EXAMPLE 108 R¹=CH₂C₃H₅; R³=(R)—COCH(CH₂OH)NHCO₂t-BuN-(2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1R)-1-(hydroxymethyl)-2-oxoethyl)(tert-butoxy)carboxamide

[0573] Example 107 (2.1 gm, 3.6 mmol) was subjected to the debenzylationprocedure of Intermediate 31 to afford Example 108 as a white foam (1.75gm, 100%).

[0574] 1H-NMR (CDCl₃/CD₃OD, 400 MHz) δ: .6.83-6.71 (m, 3H), 5.70 (br d,1H), 4.55 (m, 1H), 4.09-3.38 (m, 10H), 3.83 (s, 3H), 1.44 (s, 9H), 1.33(m, 1H), 1.18 (m, 3H), 0.73 (d, 3H), 0.62 (m, 2H), 0.37 (m, 2H).

EXAMPLE 109 R¹=CH₂C₃H₅; R³=(R)—COCH(CH₂OH)NH₂1-{(3S,4S)-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2R)-2-amino-3-hydroxypropan-1-onehydrochloride

[0575] To a stirred solution of Example 108 (1.75 gm, 3.6 mmol) indioxane (16 mL) at room temperature under a drying tube was added 4N HClin dioxane (16 mL). The clear solution was stirred for 4 hours, thenconcentrated in vacuo to provide Example 109 as a tan foam (1.5 gm,97%).

[0576] 1H-NMR (400 MHz, CDCl₃) δ: 6.85-6.76 (m, 3H), 4.36 (m, 1H),4.13-3.31 (m, 10H), 3.84 (s, 3H), 1.29 (m, 1H), 1.17 and 1.12 (doublets,3H, rotomers), 1.77 and 1.75 (singlets, 3H, rotomers), 0.62 (m, 2H),0.36 (m, 2H). LRMS (Electrospray, positive): Da/e 393.4 (m+1).

EXAMPLE 110 R¹=CH₂C₃H₅; R³=(S)—COCH(OAc)C₆H₁₁2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-cyclohexyl-2-oxoethylacetate

[0577] Intermediate 67 (91 mg, 0.6 mmol) was coupled by the Hunig's baseprocedure of Intermediate 74 using (S)-(+)-acetoxyhexahydromandelic acidchloride (100 μL, 4.98 M in CH₂Cl₂, 1.7 eq) to yield Example 110 as aclear, colorless oil (89 mg, 61%). LRMS (Electrospray, positive): Da/e488.6 (m+1).

EXAMPLE 111 R¹=CH₂C₃H₅; R³=(S)—COCH(OH)C₆H₁₁1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-cyclohexyl-2-hydroxyethan-1-one

[0578] Example 110 (89 mg, 0.18 mmol) was subjected to the LiOHhydrolysis procedure of Intermediate 5 to afford Example 111 as a clear,colorless film (44 mg, 54%).

[0579]¹H NMR (400 MHz, CDCl₃) δ: 6.80-6.78 (m, 3H), 3.88-3.52 (c, 10H),3.34-3.26 (dd, 1H), 2.98 (d, 1H), 2.12 (br s, 1H), 1.77-1.10 (c, 16H),0.75-0.73 (d, 3H), 0.62-0.59 (m, 2H), 0.34-0.31 (m, 2H). LRMS(Electrospray, positive): Da/e 446.6 (m+1).

EXAMPLE 112 R¹=CH₂C₃H₅; R³=(R)—COCH(OAc)C₆H₁₁(1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-cyclohexyl-2-oxoethylacetate

[0580] Intermediate 67 (76 mg, 0.25 mmol) was coupled by the Hunig'sbase procedure of Intermediate 74 with (R)-(−)-acetoxyhexahydromandelicacid chloride (100 μL, 4.16 M in CH₂Cl₂, 1.7 eq) to give Example 112 asa clear, colorless oil (75 mg, 62%). LRMS (Electrospray, positive): Da/e488.7 (m+1).

EXAMPLE 113 R¹=CH₂C₃H₅; R³=(R)—COCH(OH)C₆H₁₁(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-cyclohexyl-2-hydroxyethan-1-one

[0581] Example 112 (75 mg, 0.15 mmol) was subjected to the LiOHhydrolysis procedure of Intermediate 5 to give Example 113 as a clear,colorless film (35 mg, 51%).

[0582]¹H NMR (400 MHz, CDCl₃) δ: 6.81-6.73 (m, 3H), 3.85-3.59 (c, 11H),2.99-2.98 (d, 1H), 2.03-1.15 (c, 17H), 0.73 (s, 3H), 0.64-0.60 (m, 2H),0.35-0.32 (m, 2H). LRMS (Electrospray, positive): Da/e 446.5 (m+1).

EXAMPLE 114 R¹=CH₂C₃H₅; R³=(R)—COCH(C₄H₉)NHCO₂CH₂PhN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-butyl-2-oxoethyl)(phenylmethoxy)-carboxamide

[0583] Intermediate 67 (41 mg, 0.013 mmol) was coupled by the Hunig'sbase procedure of Intermediate 74 with Z-D-Nle-ONp (57 mg, 0.15 mmol,1.1 eq) to give Example 114 as a clear, colorless oil (29.9 mg, 40%).LRMS (Electrospray, positive): Da/e 553.6 (m+1).

EXAMPLE 115 R¹=CH₂C₃H₅; R³=(R)—COCH(C₄H₉)NH₂(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-aminohexan-1-one

[0584] Example 114 (29.9 mg, 0.054 mmol) was subjected to thedebenzylation procedure of Intermediate 31 to give Example 115 as awhite powder (18.8 mg, 83%).

[0585]¹H NMR (400 MHz, CDCl₃) δ: 6.83-6.62 (m, 3H), 4.17-4.08 (m, 2H),3.85-3.61 (c, 9H), 3.32-3.29 (t, 1H), 3.13-3.11 (d, 1H), 2.04-1.78 (m,3H), 1.52-1.21 (c, 10H), 0.92-0.88 (t, 3H), 0.62-0.58 (m, 5H), 0.34-0.30(m, 2H). LRMS (Electrospray, positive): Da/e 419.4 (m+1).

EXAMPLE 116 R¹=CH₂C₃H₅; R³=(R)—COCH(i-Pr)NHCO₂CH₂PhN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-(methylethyl)-2-oxoethyl)(phenylmethoxy)carboxamide

[0586] Intermediate 67 (41 mg, 0.13 mmol) was coupled by the Hunig'sbase procedure of Intermediate 74 with Z-D-Val-OSu (52.2 mg, 0.15 mmol,1.1 eq) to yield Example 116 as a clear, colorless oil (64.8 mg, 89%).

[0587]¹H NMR (400 MHz, CDCl₃) δ: 7.35-7.32 (m, 5H), 6.81-6.69 (m, 3H),5.65-5.61 (t, 3H), 5.28-5.01 (m, 2H), 4.34-2.78 (m, 10H), 2.08-1.98 (m,1H), 1.31-0.91 (c, 8H), 0.71-0.68 (d, 3H), 0.64-0.59 (m, 2H), 0.38-0.31(m, 2H).

EXAMPLE 117 R¹=CH₂C₃H₅; R³=(R)—COCH(i-Pr)NH₂(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-3-methylbutan-1-one

[0588] Example 116 (64.8 mg, 0.120 mmol) was subjected to thedebenzylation procedure of Intermediate 31 to give Example 117 as aclear solid (38.9 mg, 80%).

[0589]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.77-6.59 (m, 3H),4.41 (s, 1H), 4.23-4.12 (m, 2H), 3.85-3.60 (c, 9H), 3.24 (s, 1H),3.15-3.13 (d, 1H), 2.40 (br s, 1H), 1.29-1.14 (m, 11H), 0.62-0.58 (m,5H), 0.33-0.29 (m, 2H). LRMS (Electrospray, positive): Da/e 405.5 (m+1).

EXAMPLE 118 R¹=H; R³=COCH₂SAc1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-acetylthioethan-1-one

[0590] Intermediate 70 (173 mg, 0.694 mmol) was dissolved in dioxane (2mL), and 1 M K₂CO₃ (1 mL) was added dropwise. Acetoxymercaptoacetic acidchloride (100 μL, 13.9 M in dioxane, 2 eq) was added, and the solutionwas vigorously stirred for 1 hour. The solution was diluted with EtOAc(30 mL) and the organic layers were washed with 1M K₂CO₃ (20 mL), thenbrine (20 mL). The organic layer was dried over Na₂SO₄, and concentratedin vacuo. The resulting oil was chromatographed by silica column (1:1EtOAc:hexanes), yielding a clear, colorless oil (34 mg, 13%).

[0591]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.85-6.82 (m, 3H),3.92-2.98 (c, 12H), 2.39 (s, 3H), 1.15-1.11 (t, 3H), 0.75-0.73 (d, 3H).

EXAMPLE 119 R¹-=CH₂C₃H₅; R³=COCH₂SAc1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-acetylthioethan-1-one

[0592] To a flask containing anhydrous K₂CO₃ (52 mg, 0.37 mmol, 4.0 eq)under a nitrogen atmosphere was added a solution of Example 118 (34 mg,0.093 mmol, 1 eq) in anhydrous DMF (1 mL). Cyclopropylmethyl bromide (40μL, 0.37 mmol, 4.0 eq) was added via syringe to the mixture. The slurrywas stirred at 65° C. over-night. The reaction was cooled to roomtemperature, then diluted with water (50 mL). The aqueous solution wasextracted with EtOAc (3×30 mL), and the combined organic layers werewashed with brine (50 mL), then dried over Na₂SO₄, filtered, andconcentrated in vacuo. The resulting oil was purified by preparative TLCplate (100% EtOAc), yielding a clear, colorless oil (13.9 mg, 36%).

[0593]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.10-6.75 (m, 3H),3.91-3.32 (c, 11H), 2.64-2.61 (m, 2H), 2.38-2.30 (d, 3H), 1.82-1.50 (brs, 2H), 1.38-1.04 (m, 2H), 0.75 (s, 3H), 0.58-0.55 (m, 2H), 0.27-0.23(m, 2H).

EXAMPLE 120 R¹=CH₂C₃H₅; R³=COCH₂SH1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-sulfanylethan-1-one

[0594] Example 119 (13.9 mg, 0.0329 mmol) was subjected to the LiOHhydrolysis procedure of Intermediate 5 to give a clear, colorless oil(7.2 mg, 58%).

[0595]¹H NMR (CD3OH, 400 MHz, mixture of rotomers) δ: 6.86-6.75 (m, 3H),3.83-3.11 (c, 13H), 2.60-2.56 (d, 2H), 1.39-0.85 (m, 4H), 0.76-0.74 (m,3H), 0.58-0.56 (m, 2H), 0.35-0.24 (m, 3H). LRMS (Electrospray,positive): Da/e 380.5 (m+1).

EXAMPLE 121 R¹=CH₂C₃H₅; R³=COCH₂NHCO₂CH₂PhN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoethyl)(phenylmethoxy)carboxamide

[0596] Intermediate 67 was acylated by the Hunig's base procedure ofIntermediate 74 with N-CBZ-glycine p-nitrophenyl ester to give Example121.

[0597]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.42-7.28 (m, 5H),6.83-6.75 (m, 3H), 5.87-5.80 (m, 1H), 5.13 (s, 2H), 4.08-3.15 (c, 13H),1.39-1.24 (m, 1H), 1.14 (t, 3H), 0.73 (d, 3H), 0.66-0.59 (m, 2H),0.39-0.31 (m, 2H).

EXAMPLE 122 R¹=CH₂C₃H₅; R³=COCH₂NH₂1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-aminoethan-1-one

[0598] Example 121 was subjected to the debenzylation procedure ofIntermediate 31 to give Example 122.

[0599]¹H NMR (Methanol-d₄, 400 MHz, mixture of rotomers) δ: 6.94-6.84(m, 3H), 4.01-3.27 (c, 13H), 1.29-1.18 (m, 3H), 0.79-0.73 (m, 3H),0.62-0.55 (m, 2H), 0.35-0.29 (m, 2H). LRMS (Electrospray, positive):Da/e 363.2 (m+1).

EXAMPLE 123 R¹=CH₂C₃H₅; R³=COCH₂NHSO₂CH₃1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-[(methylsulfonyl)amino]ethan-1-one

[0600] Acylation of Example 122 by the Hunig's base coupling procedureof Intermediate 74 using methanesulfonyl chloride afforded Example 123.

[0601]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.86-6.75 (m, 3H),5.48-5.42 (m, 1H), 4.00-3.57 (c, 11H), 3.46 and 3.15 (d and d, 1H), 3.00(s, 3H), 1.67 (dd, 1H), 1.36-1.24 (m, 1H), 1.16 (t, 3H), 0.76 (d, 3H),0.66-0.60 (m, 2H), 0.39-0.32 (m, 2H). LRMS (Electrospray, positive):Da/e 441.3 (m+1).

EXAMPLE 124 R¹=CH₂C₃H₅; R³=COCH₂NHSO₂CF₃1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-{[(trifluoromethyl)sulfonyl]amino}ethan-1-one

[0602] Sulfonation of Example 122 by the Hunig's base coupling procedureof Intermediate 74 using trifluoromethanesulfonyl chloride affordedExample 124.

[0603]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.85-6.77 (m, 3H),4.11-3.10 (c, 13H), 1.15 (t, 3H), 0.76 (d, 3H), 0.66-0.60 (m, 2H),0.40-0.32 (m, 2H). LRMS (Electrospray, positive): Da/e 495.3 (m+1).

EXAMPLE 125 R¹=CH₂C₃H₅; R³=COCH₂NMe₂1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(dimethylamino)ethan-1-one

[0604] Solid Phase EDCI Coupling Reaction

[0605] A reaction vial equipped with a stir vane was charged with EDCresin (164 mg, 0.082 mmol, 0.5 mmol/g), NMP (2 mL), andN,N-dimethylglycine (20 mg, 0.143 mmol). The resulting mixture wasallowed to stir at room temperature for one hour. Intermediate 67 thenwas added, and the mixture was stirred at room temperature for 20 hours,then filtered. The resin was washed with several portions of NMP. Allthe washings and filtrate were combined and subjected to reducedpressure to remove the solvent. Biotage purification on the residue (12Scartridge, 5% MeOH/CH₂Cl₂/0.1% NH₄OH) afforded 8 mg (25%) of a clearfilm.

[0606]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.87-6.72 (m, 3H),4.07-2.97 (c, 13H), 2.35 (d, 6H), 1.35-1.25 (m, 1H), 1.17 (t, 3H), 0.74and 0.64 (s and s, 3H), 0.66-0.60 (m, 2H), 0.37-0.32 (m, 2H). LRMS(Electrospray, positive): Da/e 391.5 (m+1).

EXAMPLE 126 R¹=CH₂C₃H₅; R³=(S)—COCH(Me)NHCO₂CH₂PhN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-methyl-2-oxoethyl)(phenylmethoxy)-carboxamide

[0607] Acylation of Intermediate 67 by the solid phase EDCI procedure ofExample 125 with Z-Ala-ONp afforded Example 126.

[0608]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.38-7.26 (m, 5H),6.84-6.74 (m, 3H), 5.86 (dd 1H), 5.14-5.08 (m, 2H), 4.56 (quintet, 1H),3.87-3.32 (c, 11H), 1.43-1.34 (dd, 3H), 1.33-1.24 (m, 1H), 1.13 (d, 3H),0.74 (s, 3H), 0.66-0.59 (m, 2H), 0.37-0.32 (m, 2H). LRMS (Electrospray,positive): Da/e 511.7 (m+1).

EXAMPLE 127 R¹=CH₂C₃H₅; R³=(S)—COCH(CH₃)NH₂1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-aminopropan-1-one

[0609] Example 126 was subjected to the procedure of Intermediate 31 toafford Example 127.

[0610]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 8.44-8.16 (br s,2H), 6.82-6.56 (m, 3H), 4.53-3.02 (c, 12H), 1.43-1.34 (dd, 3H),1.33-1.24 (m, 1H), 1.13 (d, 3H), 0.74 (s, 3H), 0.66-0.59 (m, 2H),0.37-0.32 (m, 2H). LRMS (Electrospray, positive): Da/e 377.3 (m+1).

EXAMPLE 128 R¹=CH₂C₃H₅; R³=(R)—COCH(CH₃)NHCO₂CH₂PhN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-methyl-2-oxoethyl)(phenylmethoxy)-carboxamide

[0611] Prepared from Intermediate 67 via the acylation procedure ofExample 7 with Z-D-Ala-OSu.

[0612]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.28 (m, 5H),6.85-6.74 (m, 3H), 5.80 (t 1H), 5.10 (d, 2H), 4.57-4.47 (m, 1H),3.99-3.12 (c, 11H), 1.40-1.24 (m, 4H), 1.14 (d, 3H), 0.73 (s, 3H),0.66-0.59 (m, 2H), 0.38-0.31 (m, 2H). LRMS (Electrospray, positive):Da/e 511.6 (m+1).

EXAMPLE 129 R¹=CH₂C₃H₅; R³=(R)—COCH(CH₃)NH₂(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-aminopropan-1-one

[0613] Prepared from Example 128 via the debenzylation procedure ofIntermediate 31.

[0614]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 8.60-8.27 (br m,3H), 6.87-6.58 (m, 3H), 4.75-3.10 (c, 12H), 1.74-1.59 (m, 3H), 1.33-1.05(m, 4H), 0.66-0.55 (m, 5H), 0.35-0.27 (m, 2H). LRMS (Electrospray,positive): Da/e 377.2 (m+1).

EXAMPLE 130 R¹=CH₂C₃H₅; R³=(S)—COCH(i-Pr)NHCO₂CH₂PhN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-(methylethyl)-2-oxoethyl)(phenylmethoxy)carboxamide

[0615] Prepared from Intermediate 67 via the acylation procedure ofExample 7 using Z-Val-ONp.

[0616]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.42-7.27 (m, 5H),6.84-6.75 (m, 3H), 5.63 (dd 1H), 5.15-5.02 (m, 2H), 4.40-4.4.07 (dm,1H), 3.87-3.33 (c, 12H), 2.08-1.95 (m, 1H), 1.34-1.25 (m, 1H), 1.14 (t,3H), 1.04-0.90 (m, 6H), 0.73 (s, 3H), 0.66-0.59 (m, 2H), 0.38-0.31 (m,2H). LRMS (Electrospray, positive): Da/e 539.5 (m+1).

EXAMPLE 131 R¹=CH₂C₃H₅; R³=(S)—COCH(i-Pr)NH₂1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-amino-3-methylbutan-1-one

[0617] Prepared from Example 130 via the debenzylation method ofIntermediate 31.

[0618]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 8.37 (br s, 3H),6.82-6.63 (m, 3H), 4.24-3.53 (c, 11H), 3.19 (d, 1H), 2.45-2.32 (m, 2H),1.34-1.04 (m, 10H), 0.64 (s, 3H), 0.63-0.56 (m, 2H), 0.36-0.29 (m, 2H).LRMS (Electrospray, positive): Da/e 405.4 (m+1).

EXAMPLE 132 R¹=CH₂C₃H₅; R³=(S)—COCH(CH₂CH(CH₃)CH₃)NHCO₂CH₂PhN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-(2-methylpropyl)-2-oxoethyl)(phenylmethoxy)carboxamide

[0619] Prepared from Intermediate 67 via the Hunig's base acylationprocedure of Intermediate 74 using Z-Leu-ONp.

[0620]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.43-7.26 (m, 5H),6.84-6.75 (m, 3H), 5.61 (dd 1H), 5.16-5.04 (m, 2H), 4.63-4.55 (m, 1H),3.90-3.34 (c, 12H), 1.80-1.68 (m, 1H), 1.64-1.40 (m, 2H), 1.36-1.24 (m,1H), 1.14 (d, 3H), 1.05-0.92 (m, 6H) 0.74 (d, 3H), 0.65-0.59 (m, 2H),0.37-0.32 (m, 2H). LRMS (Electrospray, positive): Da/e 553.7 (m+1).

EXAMPLE 133 R¹=CH₂C₃H₅; R³=(S)—COCH(CH₂CH(CH₃)CH₃)NH₂1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-amino-4-methylpentan-1-one

[0621] Prepared from Example 132 via the debenzylation method ofIntermediate 31.

[0622]¹H NMR (Methanol-d₄, 400 MHz, mixture of rotomers) δ: 6.96-6.86(m, 3H), 4.33-4.28 (m, 1H), 4.03-3.28 (c, 11H), 1.87-1.65 (m, 3H),1.29-1.18 (m, 1H), 1.14-0.96 (m, 9H), 0.76 (d, 3H), 0.61-0.55 (m, 2H),0.36-0.29 (m, 2H). LRMS (Electrospray, positive): Da/e 419.5 (m+1).

EXAMPLE 134 R¹=CH₂C₃H₅; R³=(R)—COCH(CH₂CH(CH₃)CH₃)NHCO₂CH₂PhN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-(2-methylpropyl)-2-oxoethyl)(phenylmethoxy)carboxamide

[0623] Prepared from Intermediate 67 via the Hunig's base acylationmethod of Intermediate 74 using Z-D-Leu-ONp.

[0624]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.28 (m, 5H),6.85-6.70 (m, 3H), 5.57 (dd 1H), 5.14-5.04 (m, 2H), 4.58-4.49 (m, 1H),4.11-3.19 (c, 11H), 1.78-1.66 (m, 1H), 1.60-1.22 (m, 3H), 1.15 (dd, 3H),1.03-0.85 (m, 6H) 0.72 (d, 3H), 0.65-0.57 (m, 2H), 0.38-0.30 (m, 2H).LRMS (Electrospray, positive): Da/e 553.7 (m+1).

EXAMPLE 135 R¹=CH₂C₃H₅; R³=(R)—COCH(CH₂CH(CH₃)CH₃)NH₂(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-4-methylpentan-1-one

[0625] Prepared from Example 134 via the debenzylation method ofIntermediate 31.

[0626]¹H NMR (Methanol-d₄, 400 MHz, mixture of rotomers) δ: 6.97-6.91(m, 2H), 6.88-6.83 (m, 1H), 4.29-3.25 (c, 11H), 1.85-1.59 (m, 3H),1.30-1.19 (m, 1H), 1.10 (dd, 3H), 1.06-0.93 (m, 6H), 0.77 (dd, 3H),0.62-0.55 (m, 2H), 0.36-0.29 (m, 2H). LRMS (Electrospray, positive):Da/e 419.5 (m+1).

EXAMPLE 136 R¹=CH₂C₃H₅; R³=COCH(C₄H₉)NHCO₂CH₂PhN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-butyl-2-oxoethyl)(phenylmethoxy)carboxamide

[0627] Prepared from Intermediate 67 via the acylation method of Example7 using Z-NLeu-ONp.

[0628]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.40-7.25 (m, 5H),6.85-6.75 (m, 3H), 5.69 (dd 1H), 5.14-5.05 (m, 2H), 4.56-4.50 (m, 1H),3.87-3.34 (c, 11H), 1.80-1.54 (m, 2H), 1.43-1.24 (m, 5H), 1.14 (m, 3H),0.96-0.85 (m, 3H) 0.74 (s, 3H), 0.65-0.61 (m, 2H), 0.37-0.32 (m, 2H).LRMS (Electrospray, positive): Da/e 553.8 (m+1).

EXAMPLE 137 R¹=CH₂C₃H₅; R³=COCH(C₄H₉)NH₂1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-aminohexan-1-one

[0629] Prepared from Example 136 via the debenzylation method ofIntermediate 31.

[0630]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 6.93-6.85 (m, 3H),4.33-4.25 (m, 1H), 4.02-3.47 (c, 11H), 1.96-1.79 (m, 2H), 1.51-1.35 (m,4H), 1.30-1.19 (m, 1H), 1.11 (dd, 3H), 1.03-0.93 (m, 3H) 0.77 (d, 3H),0.62-0.56 (m, 2H), 0.35-0.30 (m, 2H). LRMS (Electrospray, positive):Da/e 419.5 (m+1).

EXAMPLE 138 R¹=CH₂C₃H₅; R³=(R)—COCH(C₆H₁₁)NH₂CO₂CH₂PhN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-(1R)-cyclohexyl-2-oxoethyl)(phenylmethoxy)carboxamide

[0631] EDCI/HOBT Coupling Procedure

[0632] A reaction vial equipped with a stir vane was charged withN-carboxybenzyl-D-cyclohexylglycine (23.8 mg, 0.0819 mmol), dry CH₂Cl₂(350 ul), EDCI (15.7 mg, 0.0819 mmol), and hydroxybenzotriazole (HOBT)(12.5 mg, 0.0819 mmol). This mixture was allowed to stir at roomtemperature for 1 hour, and Intermediate 67 (25 mg, 0.0819 mmol) wasadded in one portion. After stirring at room temperature for 48 hours,the reaction mixture was diluted with CH₂Cl₂ (5 mL), washed with 1N HCl(2×20 mL), saturated NaHCO₃ solution (1×20 ml), dried (Na₂SO₄), andconcentrated to 27 mg (57%) of a white foam.

[0633]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.39-7.29 (m, 5H),6.86-6.78 (m, 2H), 6.75-6.68 (m, 1H), 5.54 (dd, 1H), 4.37-3.25 (c, 12H),1.81.1.56 (m, 5H), 1.36-0.95 (m, 10H), 0.71 (d, 3H), 0.66-0.59 (m, 2H),0.39-0.31 (m, 2H). LRMS (Electrospray, positive): Da/e 580.2 (m+1).

EXAMPLE 139 R¹=CH₂C₃H₅; R³=(S)—COCH(C₆H₁₁)NH₂(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-2-cyclohexylethan-1-one

[0634] Prepared from Example 138 via the debenzylation procedure ofIntermediate 31.

[0635]¹H NMR (Methanol-d₄, 400 MHz, mixture of rotomers) δ: 6.95-6.78(m, 3H), 4.10-3.20 (c, 12H), 1.96-1.62 (m, 5H), 1.39-1.02 (m, 10H), 0.75(d, 3H), 0.62-0.51 (m, 2H), 0.35-0.23 (m, 2H). LRMS (Electrospray,positive): Da/e 445.5 (m+1).

EXAMPLE 140 R¹=CH₂C₃H₅; R³=(S)—COCH(t-Bu)NHCO₂CH₂PhN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-(1S)-cyclohexyl-2-oxoethyl)(phenylmethoxy)carboxamide

[0636] Prepared from Intermediate 67 via the EDCI/HOBT couplingprocedure of Example 138 using N-carboxybenzyl-L-t-butylglycine.

[0637]¹H NMR (400 MHz, CDCl₃, mixture of rotomers) δ: 7.39-7.29 (m, 5H),6.84-6.76 (m, 3H), 5.59-5.53 (m, 1H), 5.14-5.02 (m, 2H), 4.34 (dd, 1H),3.87-3.33 (c, 10H), 1.34-1.24 (m, 1H), 1.14 (dd, 3H), 0.74 (d, 3H),0.66-0.59 (m, 2H), 0.39-0.31 (m, 2H). LRMS (Electrospray, positive):Da/e 554.2 (m+1).

EXAMPLE 1411-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-amino-3,3-dimethylbutan-1-one

[0638] Prepared from Example 140 via the debenzylation procedure ofIntermediate 31.

[0639]¹H NMR (Methanol-d₄, 400 MHz, mixture of rotomers) δ: 6.98-6.86(m, 3H), 4.16-3.33 (c, 12H), 1.29-1.20 (m, 1H), 1.15-0.97 (m, 12H), 0.75(d, 3H), 0.62-0.56 (m, 2H), 0.36-0.30 (m, 2H). LRMS (Electrospray,positive): Da/e 419.5 (m+1).

EXAMPLE 1421-{(3R)-3-((1R)-1-Hydroxyethyl)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(phenylmethoxy)ethan-1-one

[0640] Intermediate 73 (775 mg, 2.53 mmol) was coupled withbenzyloxyacetyl chloride (497 μL, 3.16 mmol) by the Hunig's baseprocedure of Intermediate 74 to give Example 134 as a brown foam (978mg, 85%).

[0641]¹H-NMR (400 MHz, CDCl₃) δ: 7.41-7.30 (m, 5H), 6.90 (m, 2H), 6.81(d, 1H), 4.64 (dd, 2H), 4.15 (dd, 2H), 3.95 (dd, 1H), 3.80 (s, 3H), 3.62(dd, 1H), 3.57 (m, 2H), 3.44 (d, 1H), 3.21 (d, 1H), 1.33 (s, 9H), 1.16and 1.11 (two doublets, 3H, rotomers), 0.73 (d, 3H, rotomers).

EXAMPLE 143 R¹=H; R³=COCH₂OCH₂Ph1-[(3R)-3-((1R)-1-Hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(phenylmethoxy)-ethan-1-one

[0642] To a stirred solution of Example 142 (750 mg, 1.65 mmol) inCH₂Cl₂ (6.6 mL) at 0° C. under a drying tube was added trifluoroaceticacid (763 μL, 9.9 mmol). Cooling was removed from the reaction, and itwas allowed to warm to room temperature, then stirred for 3.5 hours. Thereaction was concentrated by rotary evaporation to remove excesstrifluoroacetic acid, then was diluted with CH₂Cl₂ (30 mL), and washedwith 10% Na₂CO₃ (2×30 mL). The organic layers were dried (MgSO₄),filtered, and concentrated in vacuo to provide Example 143. Flashchromatography in EtOAc gave, after pooling and concentration in vacuoof product containing fractions, Example 143 as a white foam (650 mg,98%).

[0643]¹H-NMR (400 MHz, CDCl₃) δ: 7.42 (m, 5H), 6.83-6.70 (m, 3H), 4.64(s, 2H), 4.16 (s, 2H), 3.93 (dd, 1H), 3.85 (s, 3H), 3.78 (d, 1H), 3.74(dd, 2H), 3.67-3.52 (m, 4H), 3.44 (d, 1H), 3.20 (d, 1H), 1.16 and 1.10(doublets, 3H, rotomers), 0.73 (s, 3H).

EXAMPLE 144 R¹=CH₂C(CH₃)(CH₂CH₂); R³=COCH₂OCH₂Ph2-Benzyloxy-1-(3-((1R)-1-hydroxyethyl)-(3S,4S)-4-[4-methoxy-3-(1-methylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl)ethanone

[0644] Solid Phase Mitsunobu Procedure

[0645] To a stirred solution of Example 143 (40 mg, 0.1 mmol) in THF(1.5 mL) at room temperature in a capped conical reaction vial was addedPS-triphenylphosphine (1.65 mmol/g, 182 mg, 0.3 mmol). After allowingthe suspension to slowly stir for 5 minutes to permit gel swelling,1-methylcyclopropaneMethanol (29 μL, 0.3 mmol) was added, and thereaction cooled to 0° C. The suspension then was treated with DIAC (59μL, 0.3 mmol), and the reaction warmed to 65° C. After stirring slowlyovernight, the reaction was cooled to room temperature and filteredthrough a polystyrene frit with THF (30 mL). The filtrate wasconcentrated in vacuo and flash chromatographed on a 15 mm×61″ columnwith 1/1/0.1 EtOAc/hexane/Methanol and product containing fractionspooled and concentrated in vacuo to provide Example 144 as a yellow oil(40 mg, 86%).

[0646]¹H-NMR (400 MHz, CDCl₃) δ: 7.42-7.25 (m, 5H), 6.83-6.77 (m, 3H),4.63 (s, 2H), 4.15 (dd, 2H), 3.96-3.20 (m, 6H, rotomers), 3.81 (s, 3H),1.74 (m, 1H), 1.24 (s, 3H), 1.17 and 1.10 (doublets, 3H, rotomers), 0.72(d, 3H, rotomers), 0.53 (m, 2H), 0.41 (m, 2H).

EXAMPLE 145 R¹=CH₂C(CH₃)(CH₂CH₂); R³=COCH₂OH1-((3R)-3-((1R)-1-Hydroxyethyl)-4-{4-methoxy-3-[(methylcyclopropyl)methoxy]phenyl}-3-methylpyrrolidinyl)-2-hydroxyethan-1-one

[0647] The crude product of Example 144 (40 mg, 0.086 mmol) wassubjected to the debenzylation procedure of Intermediate 31 to giveExample 145 as a clear oil (32.5 mg, 100%).

[0648]¹H-NMR (CDCl₃/CD₃OD, 400 MHz) δ: 6.87-6.79 (m, 3H), 3.97-3.18 (m,7H, rotomers), 3.83 (s, 3H), 1.23 (s, 3H), 1.14 and 1.11 (doublets, 3H,rotomers), 0.77 (s, 3H), 0.56 (m, 2H), 0.42 (m, 2H). LRMS (Electrospray,positive): Da/e 378.2 (m+1).

EXAMPLE 146 R¹=CH₂CH₂C₃H₅; R³=COCH₂OCH₂Ph2-Benzyloxy-1-[(3S,4S)-4-[3-(2-cyclopropylethoxy)-4-methoxyphenyl]-3-((1R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

[0649] Example 143 was subjected to the procedure of Example 144 using2-cyclopropylethanol (26 mg, 0.3 mmol) to provide Example 146 (41 mg,88%).

[0650]¹H-NMR (400 MHz, CDCl₃) δ: 7.41-7.25 (m, 5H), 6.82-6.74 (m, 3H),4.63 (s, 2H), 4.15 (dd, 2H), 4.04 (dd, 2H), 3.98-3.20 (m, 5H, rotomers),3.81 (s, 3H), 1.82 and 1.79 (m, 1H, rotomers), 1.72 (dd, 2H), 1.40-1.20(m, 1H), 1.18 and 1.12 (d, 3H, rotomers), 0.82 (m, 1H), 0.74 (s, 3H),0.46 (m, 2H), 0.12 (m, 2H).

EXAMPLE 147 R¹=CH₂CH₂C₃H₅; R³=COCH₂OH1-((3R)-3-((1R)-1-Hydroxyethyl)-4-[3-(2-cyclopropylethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one

[0651] Example 146 was subjected to the debenzylation procedure ofIntermediate 31 to provide Example 147 as a clear oil (27.4 mg, 82%).

[0652]¹H-NMR (CDCl₃/CD₃OD, 400 MHz) δ: 6.91-6.80 (m, 3H), 4.19 (m, 2H),4.10 (m, 2H), 3.97-3.15 (m, 5H, rotomers), 3.82 (s, 3H), 1.73 (dd, 2H),1.25 (m, 1H), 1.14 and 1.12 (doublets, 3H, rotomers), 0.85 (m, 1H), 0.78(s, 3H), 0.46 (m, 2H), 0.14 (m, 2H). LRMS (Electrospray, positive): Da/e378.5 (m+1).

EXAMPLE 148 R¹=CH₂CH₂C₅H₉; R³=COCH₂OH1-{(3R)-3-((1R)-1-Hydroxyethyl)-4-[3-(2-cyclopentylethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one

[0653] Prepared using the procedure of Example 144 using Example 143 and2-cyclopentylethanol (34 mg, 0.3 mmol) to provide Example 14.8 (41 mg,100%).

[0654]¹H-NMR (400 MHz, CDCl₃) δ: 7.41-7.25 (m, 5H), 6.82-6.74 (m, 3H),4.63 (s, 2H), 4.15 (dd, 2H), 3.99 (dd, 2H), 3.98-3.20 (m, 5H, rotomers),3.81 (s, 3H), 2.00-1.20 (m, 11H), 1.18 and 1.12 (d, 3H, rotomers), 0.74(s, 3H).

EXAMPLE 1491-[(3S,4S)-4-[3-(2-cyclopentylethoxy)-4-methoxyphenyl]-3-((1R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

[0655] Example 148 was subjected to the debenzylation procedure ofIntermediate 31 to afford the product as as a clear oil (34.7 mg, 86%).

[0656]¹H-NMR (CDCl₃/CD₃OD, 400 MHz) δ: 6.87-6.80 (m, 3H), 4.18 (m, 2H),4.03 (m, 2H), 3.99-3.11 (m, 5H, rotomers), 3.84 (s, 3H), 2.01-1.15 (m,11H), 1.14 and 1.11 (doublets, 3H, rotomers), 0.77 (s, 3H). LRMS(Electrospray, positive): Da/e 406.4 (m+1).

EXAMPLE 1502-Benzyloxy-1-[4-(S)-[3-(bicyclo[4.1.0]hept-7-yl-methoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

[0657] Prepared from 143 by the Mitsunobu reaction of Example 144 usingbicyclo[4.1.0]hept-7-yl-Methanol to afford an 80:20 mixture of cis andtrans isomers (34% yield).

[0658]¹H NMR (CDCl₃, 400 MHz) δ: 7.42-7.23 (m, 5H), 6.85-6.72 (m, 3H),5.06-4.89 (m, 1H), 4.67 (s, 2H), 4.15 (s, 2H), 4.07-3.56 (m, 9H),2.09-1.56 (m, 8H), 1.36-0.87 (m, 8H), 0.73 (m, 3H). LRMS (Electrospray,positive): Da/e 508.6 (m+1).

EXAMPLE 1511-[4-(S)-[3-(Bicyclo[4.1.0]hept-7-ylmethoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

[0659] Example 150 (15 mg, 30 mmol) was dissolved in 95% ethanol (1 mL)and the solution was treated with Pearlman's catalyst (20% Pd(OH)₂ oncarbon, 15 mg). The reaction mixture was hydrogenolyzed at 1 atmosphere(or at 50 psi) of hydrogen for 16 hours. The reaction mixture wasfiltered to remove the catalyst, then the solvent was removed with astream of nitrogen. The product was purified by chromatography on silicagel if necessary using EtOAc/hexanes/Methanol (1:1:0.2). (76% yield).

[0660]¹H NMR (CDCl₃, 400 MHz) δ: 6.73-6.66(m,3H), 4.04-3.99 (m,2H),3.94-3.87 (m, 4H), 3.83-3.20 (m, 7H), 3.15-2.73 (m, 1H), 1.78-1.47 (m,5H), 1.14-0.69 (10H), 0.63-0.60 (3H). LRMS (Electrospray, positive):Da/e 418.3 (m+1).

EXAMPLE 1522-Benzyloxy-1-[4-(S)-[3-(bicyclo[3.1.0]hex-6-ylmethoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

[0661] Prepared from 143 by the Mitsunobu method of Example 144 usingbicyclo[3.1.0]hex-6-yl-Methanol. The product was an inseparable mixtureof isomers at the alcohol side chain (32% yield).

[0662]¹H NMR (CDCl₃, 400 MHz) δ: 7.45-7.29 (m, 5H), 6.84-6.72 (m, 3H),5.02-4.94 (m,1H), 4.66 (s, 2H), 4.16 (s, 2H), 4.08-3.44 (m, 8H),1.96-1.51 (m, 4H), 1.26 (d, 6H), 1.18-1.08 (dd, 5H), 0.72 (m, 3H). LRMS(Electrospray, positive): Da/e 494.4 (m+1).

EXAMPLE 1531-[4-(S)-[3-(Bicyclo[3.1.0]hex-6-ylmethoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

[0663] Prepared from Example 152 by the dibenzylation method of Example151(90% yield).

[0664]¹ H NMR (CD₃OD, 400 MHz) δ: 6.87-6.79 (m, 3H), 4.97-4.90 (m, 1H),4.19-4.14 (m, 2H),3.99-3.36 (m, 7H), 3.30-2.89 (m, 1H), 1.92-1.52 (m,4H), 1.28 (d, 6H), 1.16-1.06 (m, 6H), 0.77 (m, 3H). LRMS (Electrospray,positive): Da/e 404.3(m+1).

EXAMPLE 1542-Benzyloxy-1-[4-(S)-[3-(4-tert-butylcyclohexyloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

[0665] Prepared by the Mitsunobu method of Example 144 using Example 143and 4-tert-butyl-cyclohexanol (17% yield).

[0666]¹H NMR (CDCl₃, 400 MHz) δ: 7.43-7.28 (m, 5H), 6.85-6.73 (m, 3H),6.37 (brd s, 1H), 5.02-4.93 (m, 2H), 4.67 (s, 2H), 4.13 (m, 2H),3.89-3.43 (m, 7H), 2.19-1.36 (m, 8H), 1.26 (d, 9H), 1.18-1.08 (dd, 1H),0.92-0.81 (m, 6H). LRMS (Electrospray, positive): Da/e 538.8 (m+1).

EXAMPLE 1551-[4-(S)-[3-(4-tert-Butylcyclohexyloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

[0667] Prepared from Example 154 by the dibenzylation procedure ofExample 151 (89% yield).

[0668]¹H NMR (CD₃OD, 400 MHz) δ: 6.82-6.74 (m, 3H), 4.91-4.85 (m, 3H),3.82-3.78 (m, 4H), 3.76-3.30 (m, 4H), 2.14-1.34 (m, 2H), 1.22-1.18 (m,10H), 1.08-0.99 (m, 3H), 0.86-0.78 (m, 9H), 0.79-0.75 (m, 3H). LRMS(Electrospray, positive): Da/e 448.8(m+1).

EXAMPLE 1562-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-methylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

[0669] Prepared from Example 143 by the Mitsunobu procedure using4-methylcyclohexanol (mixture of isomers) (10% yield).

[0670]¹H NMR (CDCl₃, 400 MHz) δ: 7.42-7.28 (m, 5H), 6.83-6.74 (m, 3H),4.67 (s, 2H), 4.40-4.36 (m, 1H), 4.15-4.12 (m, 2H), 3.97-3.44 (m, 8H),1.98-1.91 (m, 2H), 1.60-0.85 (m, 15H), 0.74-0.71 (d, 3H). LRMS(Electrospray, positive): Da/e 496.7 (m+1).

EXAMPLE 1572-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-methylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

[0671] Prepared from Example 156 by the debenzylation procedure ofExample 151 (quantitative yield).

[0672]¹H NMR (CD₃OD, 400 MHz) δ: 6.87-6.79 (m, 3H), 4.18-4.11 (m, 2H),3.98-3.70 (m, 1H), 3.69-3.36 (m, 10H), 3.09-2.89 (m, 1H), 1.99-1.92 (m,1H), 1.61-1.43 (m, 6H), 1.28-1.25 (m, 2H), 1.14-1.10 (m, 3H), 0.97-0.86(m, 3H), 0.78-0.76 (m, 3H). LRMS (Electrospray, positive): Da/e 406.6(m+1).

EXAMPLE 1582-Benzyloxy-1-[4-(S)-[3-(decahydronaphthalen-2-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

[0673] Prepared from Example 143 by the Mitsunobu procedure usingdecahydronaphthalen-2-ol (mixture of isomers) (10% yield).

[0674]¹H NMR (CDCl₃, 400 MHz) δ: 7.42-7.29 (m, 5H), 6.85-6.74 (m, 3H),5.03-4.95 (m, 1H), 4.68 (s, 2H), 3.98-3.45 (m, 7H), 1.90-1.10 (m, 22 H),0.75-0.72 (m, 3H) LRMS (Electrospray, positive): Da/e 536.7 (m+1).

EXAMPLE 1591-[4-(S)-[3-(Decahydronaphthalen-2-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

[0675] Prepared from Example 158 by the debenzylation procedure ofExample 151 (quantitative yield).

[0676]¹H NMR (CDCl₃, 400 MHz) δ: 6.85-6.79 (m, 3H), 5.02-4.94 (m, 1H),4.23-4.12 (m, 2H), 4.03-3.48 (m, 10H), 3.08-2.89 (m, 1H), 1.89-1.80 (m,2H), 1.78-1.13 (m, 17H), 0.77-0.75 (m, 3H) LRMS (Electrospray,positive): Da/e 446.1 (m+1).

EXAMPLE 1602-Benzyloxy-1-[4-(S)-[3-(bicyclohexyl-4-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

[0677] Prepared from Example 143 by the Mitsunobu procedure usingbicyclohexyl-4-ol (mixture of isomers) (12% yield).

[0678]¹H NMR (CDCl₃, 400 MHz) δ: 7.42-7.29 (m, 5H), 6.84-6.74 (m, 3H),5.03-4.95 (m, 1H), 4.68 (s, 2H), 4.17-4.11 (m, 2H), 3.98-3.45 (m, 7H),1.90-1.10 (m, 26H), 0.75-0.72 (m, 3H). LRMS (Electrospray, positive):Da/e 564.8 (m+1).

EXAMPLE 1611-[4-(S)-[3-(Bicyclohexyl-4-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

[0679] Prepared from Example 160 by the debenzylation procedure ofExample 151 (quantitative yield).

[0680]¹H NMR (CDCl₃, 400 MHz) δ: 6.85-6.79 (m, 3H), 5.02-4.93 (m, 1H),4.20-4.15 (m, 2H), 4.07-3.47 (m, 8H), 3.07-2.88 (m, 1H), 2.17-1.94 (m,2H), 1,82-0.82 (m, 23H), 0.77-0.74 (brd s, 3H). LRMS (Electrospray,positive): Da/e 474.6 (m+1).

EXAMPLE 1622-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-trifluoromethylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

[0681] Prepared from Example 143 by the Mitsunobu procedure using4-trifluoromethylcyclohexanol (mixture of isomers) (40% yield).

[0682]¹H NMR (CDCl₃, 400 MHz) δ: 7.46-7.24 (m, 5H), 6.88-6.77 (m, 3H),4.72-4.61 (brd s, 2H), 5.03-4.89 (brd m, 1H), 4.19-3.18 (m, 10H),2.26-0.80 (m, 14H), 0.75-0.68 (brd, 3H). LRMS (Electrospray, positive):Da/e 550.7 (m+1).

EXAMPLE 1632-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-trifluoromethylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

[0683] Prepared from Example 162 by the debenzylation procedure ofExample 151 (quantitative yield).

[0684]¹H NMR (CDCl₃, 400 MHz) δ: 6.85-6.83 (m, 3H), 5.03-4.90 (m, 1H),4.26-4.15 (m, 2H), 4.13-3.95 (m, 2H), 3.89-3.37 (m, 7H), 3.10-2.90 (m,1H), 2.26-2.18 (m, 2H), 2.08-2.01 (m, 3H), 1.55-0.86 (m, 7H), 0.75 (s,3H). LRMS (Electrospray, positive): Da/e 460.3(m+1).

EXAMPLE 1642-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(3-methoxy-3-methylbutoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

[0685] Prepared from Example 143 by the Mitsunobu procedure using3-methoxy-3-methylbutanol (78% yield).

[0686]¹H NMR (CDCl₃, 400 MHz) δ: 7.42-7.29 (m, 5H), 6.85-6.72 (m, 3H),4.67 (s, 2H), 4.17-4.13 (m, 3H), 3.97-3.45 (m, 9H), 3.23 (d, 4H),2.07-2.01 (m, 2H), 1.23 (s, 6H), 1.16-1.09 (dd, 4H), 0.72 (d, 3H). LRMS(Electrospray, positive): Da/e 500.6 (m+1).

EXAMPLE 1652-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(3-methoxy-3-methylbutoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

[0687] Prepared from Example 164 by the debenzylation method of Example151 (97% yield).

[0688]¹H NMR (CDCl₃, 400 MHz) δ: 6.83-6.72 (m, 3H), 4.19-4.11 (m, 4H),4.01-3.79 (m, 1H), 3.83 (s, 3H), 3.72-3.46 (m, 7H), 3.22 (s, 3H),2.05-1.99 (m, 2H), 1.22 (brd s, 7H), 1.16-1.11 (m, 3H), 0.73 (brd s,3H). LRMS (Electrospray, positive): Da/e 410.2 (m+1).

EXAMPLE 1662-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phenylcyclopentylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

[0689] Prepared from Example 143 by the Mitsunobu procedure using(1-phenylcyclopentyl)Methanol (25% yield)

[0690]¹H NMR (CDCl₃, 400 MHz) δ: 7.46-7.13 (m, 10H), 6.78-6.37 (m, 3H),5.01-4.93 (m, 1H), 4.66 (s, 2H), 4.15-4.10 (m, 2H), 3.92-3.41 (m, 7H),2.24-2.15 (m, 1H), 2.04-1.97 (m, 2H), 1.84-1.70 (m, 4H), 1.26 (d, 6H),1.13-1.05 (dd, 3H), 0.87-0.85 (m, 1H), 0.65 (2H). LRMS (Electrospray,positive): Da/e 558.5 (m+1).

EXAMPLE 1672-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phenylcyclopentylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

[0691] Prepared from Example 166 by the debenzylation procedure ofExample 151 (26% yield).

[0692]¹H NMR (CDCl₃, 400 MHz) δ: 7.46-7.43 (m, 2H), 7.34-7.27 (m, 2H),7.23-7.18 (m, 1H), 6.81-6.71 (m, 3H), 6.53-6.48 (m, 1H), 4.15-4.09 (m,2H), 3.93-3.88 (m, 2H), 3.78-3.46 (m, 7H), 2.25-0.68 (m, 17H). LRMS(Electrospray, positive): Da/e 468.7 (m+1).

EXAMPLE 1682-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phenylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

[0693] Prepared from Example 143 by the Mitsunobu procedure using(1-phenylcyclopropyl)Methanol (90% yield).

[0694]¹H NMR (CDCl₃, 400 HMz) δ: 7.46-7.16 (m, 10H), 6.79-6.72 (m, 2H),6.64-6.59 (m, 1H), 4.66 (s, 2H), 4.14-4.12 (m, 2H), 4.10-4.02 (m, 2H),3.91-3.42 (m, 9H), 1.28-1.25 (m, 1H), 1.14-1.06 (m, 3H), 1.04-0.95 (m,4H), 0.66 (s, 3H). LRMS (Electrospray, positive): Da/e 530.7 (m+1).

EXAMPLE 1692-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phenylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

[0695] Prepared from Example 168 by the debenzylation procedure ofExample 151 (44% yield).

[0696]¹H NMR (CDCl₃, 400 HMz) δ: 7.47-7.21 (m, 5H), 6.84-6.60 (m, 3H),4.15-4.04 (m, 4H), 3.99-3.46 (m, 8H), 3.05-2.99 (m, 1H), 2.11-2.04 (m,1H), 1.74-1.59 (m, 2H), 1.29-0.96 (m, 4H), 0.88-0.68 (m, 4H). LRMS(Electrospray, positive): Da/e 440.1(m+1).

EXAMPLE 170 R¹=CH₂C(CH₂CH₃)(CH₂OCH₂); R³=COCH₂OCH₂Ph2-Benzyloxy-1-[(3S,4S)-4-3-(3-ethyloxetan-3-ylmethoxy)-4-methoxyphenyl]-3-((1R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

[0697] Prepared from Example 143 according to the procedure in Example144 using 3-ethyl-3-oxetaneMethanol (34 mL, 0.3 mmol) to yield Example150 (44 mg, 88%).

[0698]¹H-NMR (400 HMz, CDC₃) δ: 7.41-7.25 (m, 5H), 6.84-6.80 (m, 3H),4.64 (s, 2H), 4.58 (dd, 2H), 4.49 (d, 2H), 4.17-4.11 (m, 3H), 3.99 (dd,2H), 3.98-3.20 (m, 5H, rotomers), 3.80 (s, 3H), 1.91 (dd, 2H), 1.80 (d,1H), 1.24 (dd, 1H), 1.17 and 1.13 (doublets, 3H, rotomers), 0.94 (t,3H), 0.73 (s, 3H).

EXAMPLE 171 R¹=CH₂C(CH₂CH3)(CH₂OCH₂); R³=COCH₂OH1-((3R)-3-((1R)-1-Hydroxyethyl)-4-{3-[(3-ethyloxetan-3-yl)methoxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-hydroxyethan-1-one

[0699] Example 170 was deprotected using the debenzylation ofIntermediate 31 to provide Example 171 as a clear oil (28.6 mg, 80%).

[0700]¹H-NMR (CDCl₃/CD₃OD, 400 HMz) δ: 6.91-6.83 (m, 3H), 4.64 (d, 1H),4.19 (m, 2H), 4.12 (m, 1H), 4.00-3.14 (m, 12H), 3.83 (s, 3H), 1.15 (m,3H), 0.96 (m, 3H), 0.78 (s, 3H). LRMS (Electrospray, positive): Da/e408.5 (m+1).

EXAMPLE 172 R¹=t-Bu; R³=COCH₂OAc(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoethylacetate

[0701] Prepared from Intermediate 73 via the Hunig's base couplingprocedure of Intermediate 74 using acetoxyacetyl chloride.

[0702]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 6.94-6.81 (m, 3H),4.72-4.58 (m, 2H), 3.80 (m, 3H), 3.97-3.17 (m, 6H), 2.19 (s, 3H), 1.33(d, 9H), 1.15 (t, 3H), 0.76 (d, 3H).

EXAMPLE 173 R¹=H; R³=COCH₂OAc2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoethylacetate

[0703] Example 172 was deprotected by the TFA method of Example 143 toafford Example 173 as a tan foam (173 mg, 80%).

[0704]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 6.86-6.70 (m, 3H),5.64 (br s, 1H), 4.72-4.62 (m, 2H), 3.88 (m, 3H), 3.95-3.18 (c, 6H),2.20 (d, 3H), 1.15 (t, 3H), 0.77 (d, 3H). LRMS (Electrospray, positive):Da/e 352.2 (m+1).

EXAMPLE 174 R¹=4-Ph-Ph-CH₂CH₂; R³=C(═O)CH₂OCH₂Ph2-Benzyloxy-1-[(3S,4S)-4-[3-(2-biphenyl-4-ylethoxy)-4-methoxyphenyl]-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone

[0705] Example 143 (60 mg, 0.15 mmol) was subjected to the Mitsunobuprocedure of Example 144 using 4-hydroxy-ethylbiphenyl (90 mg, 0.45mmol) and used without further purification or characterization (73 mg,84%).

EXAMPLE 175 R¹=4-Ph-Ph-CH₂CH₂; R³=C(═O)CH₂OH1-[(3S,4S)-4-[3-(2-Biphenyl-4-ylethoxy)-4-methoxyphenyl]-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

[0706] Example 174 was subjected to the debenzylation procedure ofIntermediate 31 to afford Example 175.

[0707] 1H NMR (300 HMz, CDCl₃, mixture of rotomers) δ: 7.58 (br t, 7.4Hz, 3 H), 7.47-7.27 (m, 6H), 6.86-6.77 (m, 3H), 4.24 (dt, J=3.0, 7.4 Hz,2H), 4.11 (br t, J=4.1 Hz, 2 H), 4.01-3.47 (m, 5.5H, rotomers), 3.87 (s,3H), 3.20 (t, J=7.4 Hz, 2H), 3.03 (d, J=9.8 Hz, 0.5 H, rotamer),1.36/1.32 (2d, J=3.6/3.7 Hz, 1H), 1.16/1.13 (2D, J=6.5/6.4 Hz, 3H), 0.74(s, 3H). LRMS (Electrospray, positive): m/e 490 (m+H)⁺.

EXAMPLE 176 R¹=CH₂C≡CPh; R³=COCH₂OAc2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-oxoethylacetate

[0708] A round bottom flask equipped with a stir bar and condenser wascharged with the compound of Example 173 (270 mg, 0.769 mmol), acetone(5 mL), CsCO₃ (376 mg, 1.15 mmol), and Intermediate 90 (242 mg, 1.15mmol) under a nitrogen atmosphere. The mixture was refluxed for 4 hours,then allowed to cool to room temperature. The acetone was removed underreduced pressure, and the residue taken up in EtOAc/water. The resultingmixture was extracted with EtOAc (2×100 mL), dried (Na₂SO₄), andconcentrated. Biotage purification (40 M cartridge, 1:1:0.1EtOAc:hexane:-MeOH) afforded 146 mg of Example 176 as a white foam(41%).

[0709]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.41-7.26 (m, 5H),7.05 (dd, 1H), 6.85 (d, 2H), 5.05-4.95 (m, 2H), 4.70-4.58 (m, 2H), 3.88(d, 3H), 3.95-3.13 (c, 6H), 2.19 (s, 3H), 0.97-0.92 (dd, 3H), 0.71 (d,3H). LRMS (Electrospray, positive): Da/e 466.4 (m+1).

EXAMPLE 177 R¹=CH₂C≡C-4-FPh; R³=COCH₂OAc2-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-oxoethylacetate

[0710] Prepared from Example 173 by the method of Example 176 usingIntermediate 91 as the alkylating agent.

[0711]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.40-7.36 (m, 2H),7.04-6.97 (m, 3H), 6.86-6.85 (m, 2H), 4.98-4.97 (m, 2H), 4.71-4.59 (m,2H), 3.88 (d, 3H), 3.96-3.16 (c, 6H), 2.20-2.18 (m, 3H), 1.01 (t, 3H),0.72 (d, 3H). LRMS (Electrospray, positive): Da/e 484.8 (m+1).

EXAMPLE 178 R¹=CH(C₃H₅)C₃H₅; R³=COCH₂OAc2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(dicyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoethylacetate

[0712] Prepared from Example 173 by the Mitsunobu method of Example 144using dicyclopropylcarbinol.

[0713]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.26-6.78 (m, 3H),4.74-4.60 (m, 2H), 3.96-3.46 (m, 9H), 3.21-3.10 (m, 2H), 2.20 (s, 3H),1.26 (d, 1H), 1.19-1.11 (m, 4H), 0.75 (d, 3H), 0.55-0.41 (m, 4H),0.33-0.24 (m, 4H). LRMS (Electrospray, positive): Da/e 446.5 (m+1).

EXAMPLE 179 R¹=3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)methyl;R³=CoCH₂OAc2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoethylacetate

[0714] Prepared from Example 173 via the CsCO₃ method of Example 176using Intermediate 87.

[0715]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 8.02 (d, 2H), 7.46(d, 2H), 6.95-6.85 (m, 3H), 5.40 (d, 2H), 4.70-4.58 (m, 2H), 3.94 (d,3H), 3.95-3.12 (c, 6H), 2.19 (s, 3H), 1.04-1.00 (dd, 3H), 0.64 (d, 3H).LRMS (Electrospray, positive): Da/e 544.4 (m+1).

EXAMPLE 180 R¹=CH₂C≡CPh; R³=COCH₂OH1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one

[0716] Prepared from Example 176 via the LiOH hydrolysis procedure ofIntermediate 5.

[0717]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.40-7.26 (m, 5H),7.07-7.06 (m, 1H), 6.85-6.84 (m, 2H), 5.05-4.94 (m, 2H), 3.89 (s, 3H),4.13-2.99 (c, 8H), 0.98-0.92 (dd, 3H), 0.71 (s, 3H). LRMS (Electrospray,positive): Da/e 424.6 (m+1).

EXAMPLE 181 R¹=CH₂C≡C-4-FPh; R³=COCH₂OH1-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-hydroxyethan-1-one

[0718] Prepared from Example 177 via the LiOH hydrolysis procedure ofIntermediate 5.

[0719]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.39-7.36 (m, 2H),7.03-6.98 (m, 3H), 6.85 (s, 2H), 5.02-4.93 (m, 2H), 3.89 (s, 3H),4.15-3.01 (c, 8H), 1.04-0.99 (dd, 3H), 0.72 (s, 3H). LRMS (Electrospray,positive): Da/e 442.7 (m+1).

EXAMPLE 182 R¹=C₃H₅CHC₃H₅; R³=COCH₂OH1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(dicyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one

[0720] Prepared from Example 178 by the LiOH hydrolysis procedure ofIntermediate 5.

[0721]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 6.90-6.78 (m, 3H),4.17-3.44 (c, 11H), 3.15-3.03 (m, 2H), 1.32-1.20 (m, 1H), 1.19-1.09 (m,4H), 0.75 (d, 3H), 0.54-0.39 (m, 4H), 0.34-0.23 (m, 4H). LRMS(Electrospray, positive): Da/e 404.5 (m+1).

EXAMPLE 183 R¹=3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)methyl;R³=COCH₂OH1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyethan-1-one

[0722] Prepared from Example 179 via the LiOH hydrolysis procedure ofIntermediate 5.

[0723]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 8.03 (d, 2H), 7.47(d, 2H), 6.95-6.86 (m, 3H), 5.40 (s, 2H), 3.88 (s, 3H), 4.12-2.98 (c,8H), 1.05-0.99 (dd, 3H), 0.64 (d, 3H). LRMS (Electrospray, positive):Da/e 502.4 (m+1).

EXAMPLE 184 R¹=CH₂CH₂t-Bu; R³=COCH₂OCH₂Ph1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(3,3-dimethylbutoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(phenylmethoxy)ethan-1-one

[0724] Prepared from Example 143 via the Mitsunobu method of Example 144using 3,3-dimethyl-1-butanol.

[0725]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.41-7.31 (m, 5H),6.80-6.75 (m, 3H), 4.70-4.63 (m, 2H), 4.15-3.21 (c, 13H), 1.80-1.73 (m,2H), 1.17-1.10 (m, 2H), 0.98 (s, 9H), 0.74 (d, 3H). LRMS (Electrospray,positive): Da/e 484.6 (m+1).

EXAMPLE 185 R¹=CH₂CH₂t-Bu; R³=COCH₂OH1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(3,3-dimethylbutoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one

[0726] Prepared from Example 184 via the debenzylation method ofIntermediate 31.

[0727]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 6.88-6.71 (m, 3H),4.38-2.99 (c, 13H), 1.82-1.73 (m, 2H), 1.19-1.08 (m, 3H), 0.97 (s, 9H),0.80-0.69 (m, 3H). LRMS (Electrospray, positive): Da/e 394.4 (m+1).

EXAMPLE 186 R¹=CH₂C₃H₅; R³=COCH₂OCH₂Ph1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(phenylmethoxy)ethan-1-one

[0728] Prepared from Intermediate 67 via the Hunig's base couplingmethod of Intermediate 74 using benzyloxy-acetyl chloride.

[0729]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.40-7.29 (m, 5H),6.82-6.74 (m, 3H), 4.66 (s, 2H), 4.15-3.20 (c, 11H), 1.71-1.57 (br s,1H), 1.35-1.23 (m, 1H), 1.16-1.07 (dd, 3H), 0.71 (s, 3H), 0.62 (d, 2H),0.34 (d, 2H). LRMS (Electrospray, positive): Da/e 454.6 (m+1).

EXAMPLE 187 R¹=CH₂C₃H₅; R³=COCH₂OH1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one

[0730] Prepared from Example 186 via the debenzylation method ofIntermediate 31.

[0731]¹H NMR (Methanol-d₄, 400 HMz) δ: 6.95-6.84 (m, 3H), 4.31-4.22 (m,2H), 3.91-3.23 (c, 11H), 1.30-1.19 (m, 1H), 0.74 (s, 3H), 0.62-56 (m,2H), 0.35-0.28 (m, 2H). LRMS (Electrospray, positive): Da/e 364.2 (m+1).

EXAMPLE 188 R¹=CH₂C₃H₅; R³=COCH₂NHCO₂CH₂PhN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoethyl)(phenylmethoxy)carboxamide

[0732] Prepared from Intermediate 67 via the acylation procedure ofExample 7 using Z-Gly-ONp.

[0733]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.45-7.30 (m, 5H),6.85-6.76 (m, 3H), 5.81 (br s, 1H), 5.13 (s, 2H), 4.10-3.43 (c, 12H),3.17 (d, 1H), 1.68 (br s, 1H), 1.36-1.26 (m, 1H), 1.14 (t, 3H), 0.73 (d,3H), 0.66-0.60 (m, 2H), 0.38-0.31 (m, 2H).

EXAMPLE 189 R¹=CH₂C₃H₅; R³=COCH₂NH₂1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-aminoethan-1-one

[0734] Prepared from Example 188 via the debenzylation procedure ofIntermediate 31.

[0735]¹H NMR (Methanol-d₄, 400 HMz, mixture of rotomers) δ: 6.96-6.81(m, 3H), 4.00-3.27 (c, 13H), 1.29-1.18 (m, 1H), 1.13-1.07 (m, 3H), 0.75(m, 3H), 0.62-54 (m, 2H), 0.35-0.28 (m, 2H). LRMS (Electrospray,positive): Da/e 363.2 (m+1).

EXAMPLE 190 R¹=CH₂C₃H₅; R³=COC(CH₃)₂OCOCH₃2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1,1-dimethyl-2-oxoethylacetate

[0736] Prepared from Intermediate 67 via the Hunig's base couplingprocedure of Intermediate 74 using 2-acetoxyisobutyryl chloride.

[0737]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 6.87-6.70 (m, 3H),3.93-3.32 (c, 11H), 2.08 (d, 3H), 1.81-1.65 (br m, 1H), 1.65-1.53 (m,6H), 1.35-1.23 (m, 1H), 1.19-1.11 (t, 3H), 0.68 (d, 3H), 0.65-0.57 (m,2H), 0.37-0.30 (m, 2H).

EXAMPLE 191 R¹=CH₂C₃H₅; R³=COC(CH₃)₂OH1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy),-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxy-2-methylpropan-1-one

[0738] Prepared from Example 190 via the LiOH hydrolysis procedure ofIntermediate 5.

[0739]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 6.84-6.75 (m, 3H),4.43 (br s, 1H), 4.01-3.41 (c, 11H), 1.52-1.41 (m, 6H), 1.32-1.17 (m,1H), 1.16-1.08 (t, 3H), 0.73 (d, 3H), 0.63-0.57 (m, 2H), 0.37-0.29 (m,2H). LRMS (Electrospray, positive):. Da/e 392.5 (m+1).

EXAMPLE 192 R¹=CH₂C₃H₅; R³=(S)—COCH(CH₃)OAc2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-methyl-2-oxoethylacetate

[0740] Prepared from Intermediate 67 via the Hunig's base couplingprocedure of Intermediate 74 using (S)-2-acetoxypropionyl chloride.

[0741]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 6.83-6.76 (m, 3H),5.25-5.17 (m, 1H), 4.08-3.35 (c, 12H), 2.15-2.09 (m, 3H), 1.50-1.44 (m,3H), 1.35-1.23 (m, 1H), 1.15 (d, 3H), 0.79-0.71 (m, 3H), 0.65-0.60 (m,2H), 0.37-0.30 (m, 2H).

EXAMPLE 193 R¹=CH₂C₃H₅; R³=(S)—COCH(CH₃)OH1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxypropan-1-one

[0742] Prepared from Example 192 via the LiOH hydrolysis procedure ofIntermediate 5.

[0743]¹H NMR (4.00 HMz, CDCl₃, mixture of rotomers) δ: 6.84-6.73 (m,3H), 4.39-4.28 (m, 1H), 3.88-3.48 (c, 10H), 3.29 (dd, 1H), 1.40-1.20 (m,4H), 1.12 (t, 3H), 0.73 (d, 3H), 0.64-0.55 (m, 2H), 0.37-0.29 (m, 2H).LRMS (Electrospray, positive): Da/e 378.7 (m+1).

EXAMPLE 194 R¹=CH₂C₃H₅; R³=COCH(Ph)OAc2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxo-1-phenylethylacetate

[0744] Prepared from Intermediate 67 via the Hunig's base couplingprocedure of Intermediate 74 using O-acetylmandelic acid chloride.

[0745]¹H NMR (400 HMz, CDCl₃, mixture of rotomers and diastereomers) δ:7.57-7.35 (m, 5H), 6.84-6.51 (m, 3H), 6.11-6.04 (m, 1H), 4.08-3.05 (c,11H), 2.21-2.14 (m, 3H), 1.36-1.20 (m, 1H), 1.14-1.06 (dd, 3H), 0.78 and0.48 (s and d, 3H), 0.67-0.57 (m, 2H), 0.37-0.28 (m, 2H). LRMS(Electrospray, positive): Da/e 482.6 (m+1).

EXAMPLE 195 R¹=CH₂C₃H₅; R³=COCH(Ph)OH1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxy-2-phenylethan-1-one

[0746] Prepared from Example 194 via the LiOH hydrolysis procedure ofIntermediate 5.

[0747]¹H NMR (400 HMz, CDCl₃, mixture of rotomers and diastereomers) δ:7.40-7.28 (m, 5H), 6.81-6.42 (m, 3H), 5.13-4.61 (m, 1H), 4.07-3.29 (c,10H), 3.21-2.79 (m, 1H), 1.36-1.20 (m, 1H), 1.15-0.97 (dd, 3H), 0.73 and0.47 (d and s, 3H), 0.65-0.56 (m, 2H), 0.37-0.28 (m, 2H). LRMS(Electrospray, positive): Da/e 440.2 (m+1).

EXAMPLE 196 R¹=CH₂C₃H₅; R³=COCH(4-FPh)OAc2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-(4-fluorophenyl)-2-oxoethylacetate

[0748] Prepared from Intermediate 67 via the Hunig's base couplingprocedure of Intermediate 74 using(chlorocarbonyl)(4-fluorophenyl)methyl acetate.

[0749]¹H NMR (400 HMz, CDCl₃, mixture of rotomers and diastereomers) δ:7.60-7.46 (m, 2H), 7.15-7.03 (m, 2H), 6.85-6.54 (m, 3H), 6.09-5.99 (m,1H), 4.07-2.87 (c, 11H), 2.19-2.12 (m, 3H), 1.33-1.20 (m, 1H), 1.15-1.03(dd, 3H), 0.78 and 0.52 (d and d, 3H), 0.65-0.57 (m, 2H), 0.38-0.27 (m,2H). LRMS (Electrospray, positive): Da/e 501.0 (m+1).

EXAMPLE 197 R¹=CH₂C₃H₅; R³=COCH(4-FPh)OH1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl)-3-methylpyrrolidinyl}-2-(4-fluorophenyl)-2-hydroxyethan-1-one

[0750] Prepared from Example 196 via the LiOH hydrolysis procedure ofIntermediate 5.

[0751]¹H NMR (400 HMz, CDCl₃, mixture of rotomers and diastereomers) δ:7.60-7.25 (m, 2H), 7.12-7.00 (m, 2H), 6.84-6.48 (m, 3H), 5.11-4.59 (m,1H), 4.04-2.79 (c, 11H), 1.35-1.23 (m, 1H), 1.15-1.00 (dd, 3H), 0.75 and0.48 (d and s, 3H), 0.66-0.60 (m, 2H), 0.37-0.30 (m, 2H) LRMS(Electrospray, positive): Da/e 458.2 (m+1).

EXAMPLE 198 R¹=CH₂C₃H₅; R³=COC(CH₂CH₂)OAc({3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-carbonyl)cyclopropylacetate

[0752] Prepared from Intermediate 67 via the Hunig's base couplingprocedure of Intermediate 74 using (chlorocarbonyl)cyclopropyl acetate.

[0753]¹H NMR (400 HMz, CDCl₃) δ: 6.85-6.72 (m, 3H), 4.06-3.31 (c, 11H),2.10 (s, 3H), 1.74-1.62 (m, 1H), 1.59-1.47 (m, 1H), 1.35-1.19 (m, 2H),1.14 (d, 3H), 1.02-0.93 (m, 1H), 0.71 (s, 3H), 0.65-0.59 (m, 2H)0.37-0.30 (m, 2H). LRMS (Electrospray, positive): Da/e 432.5 (m+1).

EXAMPLE 199 R¹=CH₂C₃H₅; R³=COC(CH₂CH₂)OH3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinylhydroxycyclopropyl ketone

[0754] Prepared from Example 198 via the LiOH hydrolysis procedure ofIntermediate 5.

[0755]¹H NMR (400 HMz, CDCl₃) δ: 6.88-6.78 (m, 3H), 4.42-3.30 (c, 11H),1.42-1.22 (m, 3H), 1.16 (d, 3H), 1.11-0.88 (m, 3H), 0.74 (d, 3H),0.66-0.59 (m, 2H), 0.39-0.31 (m, 2H). LRMS (Electrospray, positive):Da/e 390.5 (m+1).

EXAMPLE 200 R¹=CH₂C₃H₅; R³=(S)—COCH(OAc)CH(CH₃)CH₂CH₃2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-(methylpropyl)-2-oxoethylacetate

[0756] Prepared from Intermediate 67 via the Hunig's base couplingprocedure of Intermediate 74 using (1S)-1-(chlorocarbonyl)-2-methylbutylacetate.

[0757]¹H NMR (400 HMz, CDCl₃, mixture of rotomers and diastereomers) δ:6.85-6.72 (m, 3H), 4.84 (dd, 1H), 3.89-3.31 (c, 11H), 2.12 (d, 3H),2.09-1.95 (m, 1H), 1.75-1.62 (m, 1H), 1.35-1.19 (m, 2H), 1.15 (t, 3H),1.00-0.86 (m, 6H), 0.75 (d, 3H), 0.65-0.56 (m, 2H), 0.37-0.30 (m, 2H).LRMS (Electrospray, positive): Da/e 462.5 (m+1).

EXAMPLE 201 R¹=CH₂C₃H₅; R³=(S)—COCH(OH)CH(CH₃)CH₂CH₃1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxy-3-methylpentan-1-one

[0758] Prepared from Example 200 via the LiOH hydrolysis procedure ofIntermediate 5.

[0759]¹H NMR (400 HMz, CDCl₃, mixture of rotomers and diastereomers) δ:6.85-6.76 (m, 3H), 4.18-4.11 (m, 1H), 3.94-3.26 (c,-11H), 1.75-1.66 (m,1H), 1.54-1.19 (m, 4H), 1.15 (dd, 3H), 1.07 (m, 3H), 0.94-0.85 (m, 3H),0.76 (d, 3H), 0.66-0.60 (m, 2H), 0.38-0.32 (m, 2H). LRMS (Electrospray,positive): Da/e 420.5 (m+1).

EXAMPLE 202 R¹=CH₂C₃H₅; R³=(S)—COCH(OAc)CH₂CH(CH₃)₂2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-(2-methylpropyl)-2-oxoethylacetate

[0760] Prepared from Intermediate 67 via the Hunig's base couplingprocedure of Intermediate 74 using (1S)-1-(chlorocarbonyl)-3-methylbutylacetate.

[0761]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 6.84-6.74 (m, 3H),5.19-5.10 (m, 1H), 4.15-2.95 (c, 11H), 2.13 (d, 3H), 1.95-1.72 (m, 2H),1.58-1.39 (m, 2H), 1.34-1.23 (m, 1H), 1.18-1.12 (m, 3H), 1.00-0.88 (m,6H), 0.75 (d, 3H), 0.68-0.57 (m, 2H), 0.37-0.30 (m, 2H). LRMS(Electrospray, positive).: Da/e 462.5 (m+1)

EXAMPLE 203 R¹=CH₂C₃H₅; R³=(S)—COCH(OH)CH₂CH(CH₃)₂1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxy-4-methylpentan-1-one

[0762] Prepared from Example 202 via the LiOH hydrolysis procedure ofIntermediate 5.

[0763]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 6.86-6.77 (m, 3H),4.32-4.25 (m, 1H), 3.88-2.97 (c, 11H), 2.05-1.93 (m, 1H), 1.73-1.21 (m,5H), 1.14 (dd, 3H), 1.02-0.93 (m, 6H), 0.76 (d, 3H), 0.66-0.60 (m, 2H),0.38-0.32 (m, 2H). LRMS (Electrospray, positive): Da/e 420.3 (m+1).

EXAMPLE 204 R¹=CH₂C₃H₅; R³=(S)—COCH(OAc)CH₂Ph2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-2-oxo-1-benzylethylacetate

[0764] Prepared from Intermediate 67 via the Hunig's base couplingprocedure using (1S)-1-(chlorocarbonyl)-2-phenylethyl acetate.

[0765]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.40-7.26 (m, 5H),6.82-6.70 and 6.52-6.47 (m and m, 3H), 5.30-5.18 (m, 1H), 3.90-2.79 (c,13H), 2.11 (d, 3H), 1.35-1.25 (m, 1H), 1.05 (dd, 3H), 0.66 and 0.33 (sand s, 3H), 0.68-0.60 (m, 2H), 0.39-0.32 (m, 2H). LRMS (Electrospray,positive): Da/e 497.0 (m+1).

EXAMPLE 205 R¹=CH₂C₃H₅; R³=(S)—COCH(OH)CH₂Ph1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxy-3-phenylpropan-1-one

[0766] Prepared from Example 204 (20 mg, 0.040 mmol) by the LiOHhydrolysis procedure of Intermediate 5 to afford 14.5 mg (79%) ofExample 205 as a colorless film.

[0767]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.40-7.26 (m, 5H),6.82-6.75 and 6.56-6.53 (m and m, 3H), 4.51-4.43 (m, 1H), 3.90-2.70 (c,13H), 1.35-1.25 (m, 1H), 1.09 (dd, 3H), 0.69 and 0.52 (s and s, 3H),0.68-0.60 (m, 2H), 0.39-0.32 (m, 2H). LRMS (Electrospray, positive):Da/e 454.3 (m+1).

EXAMPLE 206 R¹=CH₂C₃H₅; R³=(R)—COCH(OAc)CH₂Ph(1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclo-propylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxo-1-benzylethylacetate

[0768] Prepared from Intermediate 67 via the Hunig's base couplingprocedure of Intermediate 74 using (1R)-1-(chlorocarbonyl)-2-phenylethylacetate.

[0769]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.37-7.22 (m, 5H),6.82-6.72, 6.64, 6.45 (m, d, and dd, 3H), 5.27 and 5.18 (dd, t, 1H),3.99-2.56 (c, 13H), 2.12 (s, 3H) 1.34-1.24 (m, 1H), 1.13-1.02 (dd, 3H),0.68 and 0.34 (s and s, 3H), 0.65-0.58 (m, 2H), 0.37-0.30 (m, 2H). LRMS(Electrospray, positive): Da/e 496.6 (m+1).

EXAMPLE 207 R¹=CH₂C₃H₅; R³=(R)—COCH(OH)CH₂Ph((2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclo-propylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxy-3-phenylpropan-1-one

[0770] Prepared from Example 206 via the lithium peroxide method ofIntermediate 43.

[0771]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.35-7.18 (m, 5H),6.84-6.67 (m, 3H), 4.48-4.40 (m, 1H), 4.04-2.70 (c, 13H), 1.34-1.24 (m,1H), 1.08 (dd, 3H), 0.71 and 0.49 (s and s, 3H), 0.65-0.58 (m, 2H),0.38-0.31 (m, 2H). LRMS (Electrospray, positive): Da/e 454.5 (m+1).

EXAMPLE 208 R¹=t-Bu; R³=(S)—COCH(OAc)CH₃2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-methyl-2-oxoethylacetate

[0772] Prepared from Intermediate 73 via the Hunig's base couplingprocedure of Intermediate 74 using (S)-2-acetoxypropionyl chloride.

[0773]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 6.95-6.81 (m, 3H),5.24-5.11 (m, 1H), 3.80 (m, 3H), 4.08-3.38 (m, 6H), 2.15-2.12 (d, 3H),1.49-1.46 (dd, 3H), 1.33 (d, 9H), 1.14 (d, 3H), 0.76 (d, 3H). LRMS(Electrospray, positive): Da/e 422.4 (m+1).

EXAMPLE 209 R¹=H; R³=(S)—COCH(OAc)CH₃2-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-1-methyl-2-oxoethylacetate

[0774] Prepared from Example 208 via the TFA deprotection method ofExample 143.

[0775]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 6.88-6.70 (m, 3H),5.73-5.69 (br d, 1H), 5.25-5.19 (m, 1H), 3.88 (d, 3H), 4.06-3.38 (m,6H), 2.12 (d, 3H), 1.49-1.46 (d, 3H), 1.16-1.14 (dd, 3H), 0.75 (d, 3H).LRMS (Electrospray, positive): Da/e 366.3 (m+1).

EXAMPLE 210 R¹=CH₂C≡CPh; R³=(S)—COCH(OAc)CH₃2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-(1S)-1-methyl-2-oxoethylacetate

[0776] Prepared from Example 209 via the Cs₂CO₃ method of Example 176using Intermediate 90.

[0777]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.39-7.26 (m, 5H),7.05 (d, 1H), 6.85 (s, 2H), 5.23-5.17 (m, 1H), 5.05-4.95 (m, 2H), 3.86(s, 3H), 4.07-3.36 (d, 6H), 2.15-2.12 (d, 3H), 1.47-1.40 (t, 3H),1.36-1.33 (m, 1H), 0.99-0.95 (m, 3H), 0.75-0.71 (d, 3H). LRMS(Electrospray, positive): Da/e (m+1).

EXAMPLE 211 R¹=CH₂C≡CPh; R³=(S)—COCH(OH)CH₃1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-(2S)-2-hydroxypropan-1-one

[0778] Prepared from Example 210 via the O-acetate deprotection methodof Example 95.

[0779]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.41-7.26 (m, 5H),7.07 (d, 1H), 6.86 (s, 2H), 5.05-4.94 (m, 1H), 4.36-4.30 (m, 1H), 3.89(s, 3H), 3.91-3.48 (c, 5H), 3.28 (dd, 1H), 1.37-1.32 (m, 3H) 0.99-0.92(dd, 3H), 0.73-0.70 (d.3H). LRMS (Electrospray, positive): Da/e 438.2(m+1).

EXAMPLE 212 R¹=CH₂C≡C-4-FPh; R³=(S)—COCH(OAc)CH₃2-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-oxoethylacetate

[0780] Prepared from Example 209 via the Cs₂CO₃ method of Example 176using Intermediate 91.

[0781]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.40-7.36 (m, 2H),7.03-6.96 (m, 3H), 5.22-5.20 (q, 1H), 4.98-4.96 (m, 2H), 4.07-3.53 (c,6H), 3.88-3.86 (m, 3H), 2.14-2.11 (d, 3H), 1.47-1.42 (t, 3H), 1.06-1.01(m, 3H), 0.75-0.72 (d, 3H). LRMS (Electrospray, positive): Da/e 498.5(m+1).

EXAMPLE 213 R¹=CH₂C≡C-4-FPh; R³=(S)—COCH(OH)CH₃1-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)(2S)-2-hydroxypropan-1-one

[0782] Prepared from Example 212 via the O-acetate deprotection methodof Example 95.

[0783]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.40-7.26 (m, 2H),7.04-6.98 (m, 3H), 6.86 (s, 2H), 5.03-4.97 (m, 2H), 4.40-4.30 (m, 1H),3.89 (s, 3H), 3.94-3.52 (c, 5H), 3.29 (dd, 1H), 1.39-1.28 (d, 3H),1.04-1.00 (m, 3H), 0.74-0.72 (d, 3H). LRMS (Electrospray, positive):Da/e 456.5 (m+1).

EXAMPLE 214 R¹=CH₂C≡C-4-CF₃Ph; R³=(S)—COCH(OAc)CH₃2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(4-methoxy-3-{3-[4-(trifluoromethyl)phenyl]prop-2-ynyloxy}phenyl)-3-methylpyrrolidinyl](1S)-1-methyl-2-oxoethylacetate

[0784] Prepared from Example 209 via the Cs₂CO₃ method of Example 176using Intermediate 92.

[0785]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.57-7.45 (m, 4H),7.01 (d, 1H), 6.88-6.83 (m, 2H), 5.22-5.17 (m, 1H), 5.00 (s, 2H),4.07-3.35 (c, 6H), 3.88 (d, 3H), 2.13-2.11 (d, 3H), 1.47-1.42 (dd, 3H),1.12 (d, 3H), 0.75-0.71 (d, 3H). LRMS (Electrospray, positive): Da/e548.8 (m+1).

EXAMPLE 215 R¹=CH₂C≡C-4-CF₃Ph; R³=(S)—COCH(OH)CH₃1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(4-methoxy-3-{3-[4-(trifluoromethyl)phenyl]prop-2-ynyloxy}phenyl)-3-methylpyrrolidinyl](2S)-2-hydroxypropan-1-one

[0786] Prepared from Example 214 via the O-acetate deprotection methodof Example 95.

[0787]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.56 (d, 2H), 7.50(d, 2H), 7.03 (s, 1H), 6.87 (s, 2H), 5.01 (s, 2H), 4.36-4.33 (m, 1H),3.89 (s, 3H), 3.91-3.49 (c, 5H), 3.30 (dd, 1H), 1.37-1.35 (dd, 3H),1.04-1.01 (t, 3H), 0.74-0.71 (d, 3H). LRMS (Electrospray, positive):Da/e 505.9 (m+1).

EXAMPLE 216 R¹=3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)methyl;R³=(S)—COCH(OAc)CH₃2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-1-methyl-2-oxoethylacetate

[0788] Prepared from Example 209 via the Cs₂CO₃ method of Example 176using Intermediate 87.

[0789]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 8.01 (d, 2H), 7.46(d, 1H), 6.96-6.85 (m, 3H), 5.45-5.36 (m, 2H), 5.21-5.14 (m, 1H),4.02-3.36 (c, 6H), 3.84 (m, 3H), 2.11 (d, 3H), 1.47-1.42 (m, 3H),1.04-1.02 (d, 3H), 0.67-0.65 (d, 3H). LRMS (Electrospray, positive):Da/e 558.2 (m+1).

EXAMPLE 217 R¹=3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)methyl;R³=(S)—COCH(OH)CH₃1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-hydroxypropan-1-one

[0790] Prepared from Example 216 via the O-acetate deprotection methodof Example 95.

[0791]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 8.06-8.00 (m, 2H),7.49-7.45 (m, 2H), 6.97-6.86 (m, 3H), 5.41 (m, 2H), 4.35-4.32 (m, 1H),3.88 (s, 3H) 3.86-3.19 (c, 6H), 1.38-1.32 (m, 3H), 1.05-1.00 (dd, 3H),0.66-0.63 (d, 3H) LRMS (Electrospray, positive): Da/e 516.4 (m+1).

EXAMPLE 218 R¹=2-indanyl; R³=COCH(OAc)4-FPh2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yl-oxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-(4-fluorophenyl)-2-oxoethylacetate

[0792] Intermediate 51 (72.8 mg, 0.198 mmol) was acylated by the K₂CO₃procedure of Example 7 with 2-acetoxy-fluoromandelic acid chloride (120mg, 0.297 mmol, 1.5 eq) to give a clear, colorless oil (84.2 mg, 75%).

[0793]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.53-7.47 (m, 2H),7.26-7.03 (m, 6H), 6.87-6.59 (m, 3H), 6.09-6.04 (m, 1H), 5.28-5.01 (m,1H), 4.14-3.03 (c, 13H), 2.16 (s, 3H), 1.27-1.06 (m, 3H), 0.82-0.80 (d,1.5H), 0.55-0.52 (d, 1.5H).

EXAMPLE 219 R¹=2-indanyl; R³=COCH(OH)4-FPh1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(4-fluorophenyl)-2-hydroxyethan-1-one

[0794] Example 218 (19 mg, 0.034 mmol, 1 eq) was subjected to the LiOHhydrolysis procedure of Intermediate 5 to yield a white powder (6.1 mg,35%).

[0795]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 6.97-6.80 (c, 7H),4.19 (m, 2H), 4.13 (t, 2H), 3.82 (s, 3H), 3.72 (s, 3H), 3.83-3.48 (c,4H), 3.25 (dd, 1H), 2.27 (quintet, 2H), 1.70 (s, 1H), 1.56 (br d, 1H),1.13 (t, 3H), 0.73 (s, 3H) LRMS (Electrospray, positive): Da/e 520.4(m+1).

EXAMPLE 220 R¹=2-indanyl; R³=COCH(OAc)CH₃2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-methyl-2-oxoethylacetate

[0796] Intermediate 51 (27 mg, 0.074 mmol) was acylated by the K₂CO₃procedure of Example 7 using (+)-2-acetoxy-propionyl chloride (12.1 μL,0.110 mmol, 1.5 eq) to yield a clear, colorless oil (16.7 mg, 47%). HNMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.27-7.17 (m, 4H),6.85-6.83 (m, 3H), 5.30-5.17 (m, 2H), 4.13-3.19 (c, 9H), 2.14 (s, 3H),1.72 (br s, 1H), 1.51-1.47 (m, 4H), 1.19-1.17 (d, 3H), 0.82-0.78 (d,3H).

EXAMPLE 221 R¹=2-indanyl; R³=COCH(OH)CH₃1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxypropan-1-one

[0797] Example 220 (16.7 mg, 0.0347 mmol, 1 eq) was subjected to theLiOH hydrolysis procedure of Intermediate 5 to yield a white solid (4.7mg, 31%).

[0798]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.27-7.17 (m, 4H),6.85-6.84 (m, 3H), 5.19-5.15 (m, 1H), 4.39-4.35 (m, 1H), 3.90-3.18 (c,14H), 1.57-1.37 (m, 3H), 1.28-1.15 (m, 3H), 0.80-0.78 (d, 3H). LRMS(Electrospray, positive): Da/e 440.4 (m+1).

EXAMPLE 222 R¹=2-indanyl; R³=COC(CH₃)(OAc)CH₃2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1,1-dimethyl-2-oxoethylacetate

[0799] Intermediate 51 (40 mg, 0.11 mmol) was acylated by the K₂CO₃procedure of Example 7 using 2-acetoxy-2-methylpropionyl chloride (31μL, 0.22 mmol, 2 eq) to yield a clear, colorless oil (22 mg, 40%).

[0800]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.26-7.16 (m, 4H),6.85-6.77 (m, 3H), 4.17 (m, 1H), 3.95-3.19 (c, 14H), 2.10 (s, 3H),1.65-1.57 (m, 6H), 1.20-1.17 (m, 3H), 0.73 (s, 3H).

EXAMPLE 223 R¹=2-indanyl; R³=COC(CH₃)(OH)CH₃1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxy-2-methylpropan-1-one

[0801] Example 222 (22 mg, 0.044 mmol) was subjected to the LiOHhydrolysis procedure of Intermediate 5 to yield product as a white solid(4.3 mg, 22%).

[0802]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.26-7.17 (m, 4H),6.83 (m, 3H), 5.18-5.17 (m, 1H), 4.45-4.44 (m, 1H), 3.89-3.19 (c, 14H),1.53-1.48 (m, 6H), 1.19-1.17 (m, 3H), 0.79-0.78 (d, 3H). LRMS(Electrospray, positive): Da/e 454.4 (m+1).

EXAMPLE 224 R¹=t-Bu; R³=CO₂CH₃ Methyl(3R)-3-((1R)-1-hydroxyethyl)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidine-carboxylate

[0803] Intermediate 73 (6.5 μL, 0.084 mmol) was acylated by the Hunig'sbase method of Intermediate 74 with methyl chloroformate to provideExample 224 as a yellow oil (19 mg, 94%).

[0804]¹H-NMR (400 HMz, CDCl₃) δ: 6.96 (d, 1H), 6.84 (s, 1H), 6.83 (d,1H), 3.80 (s, 3H), 3.77-3.58 (m, 4H), 3.06 (d, 1H), 1.36 (s, 9H), 1.16(d, 3H), 0.76 (s, 3H).

EXAMPLE 2252-Hydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[2-(tetrahydrofuran-2-yl)ethoxy]phenyl}-3-methylpyrrolidin-1-yl)ethanone

[0805] Prepared from Example 143 by the Mitsunobu procedure of Example144 using 2-tetrahydrofuran-2-ylethanol followed by debenzylation viathe method of Intermediate 31.

[0806]¹H NMR data δ: 6.75-6.87 (m, 3H); 4.16-4.20 (m, 2H) 4.15 (s, 3H);3.49-4.13 (m, 11H); 3.05 (d, 1H); 1.97-2.10 (m, 2H)1.88-1.96 (t, 2H);1.56-1.63 (m, 2H); 1.3-1.17 (t, 3H); 0.75 (s, 3H).

EXAMPLE 2262-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxy-ethyl)-4-[4-methoxy-3-(tetrahydrofuran-3-ylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

[0807] Prepared from Example 143 by the Mitsunobu method of Example 144using tetrahydrofuran-3-ylMethanol followed by the debenzylationprocedure of Intermediate 31.

[0808]¹H NMR data δ: 6.79-6.82 (m, 3H); 4.13-4.16 (m, 2H); 3.48-3.98 (m,11H); 3.84 (s, 3H); 3.05 (d, 1H); 2.80 (bt; 1H); 2.07-2.15 (M, 2H);1.72-1.79 (m, 1H); 1.16 (t, 3H); 0.76 (s, 3H).

EXAMPLE 227 R¹=(S)—CH(CH₂OCH₂CH₂); R³=CO₂CH₃ Methyl(3R)-3-((1R)-1-hydroxyethyl)-4-[3-((3S)-oxolan-3-yloxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylate

[0809] Prepared from Intermediate 74 (146 mg, 0.47 mmol) by the solidphase Mitsunobu procedure of Example 144 using(S)-(+)-3-hydroxytetrahydrofuran (38 μL), 0.47 mmol) to afford Example227 as a clear oil (95 mg, 53%).

[0810]¹H-NMR (400 HMz, CDCl₃) δ: 6.82 (m, 2H), 6.78 (m, 1H), 4.95 (m,1H), 4.03-3.20 (m, 10H), 3.82 (s, 3H), 3.66 (s, 3H), 2.17 (m, 2H), 1.17(t, 3H), 0.73 (s, 3H). LRMS (Electrospray, positive): Da/e 379.8 (m+1).

EXAMPLE 228 R¹=(R)—CH(CH₂OCH₂CH₂); R³=CO₂CH₃ Methyl(3R)-3-((1R)-1-hydroxyethyl)-4-[3-((3R)-oxolan-3-yloxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylate

[0811] Prepared from Intermediate 74 using the solid phase Mitsunobureaction of Example 144 and (R)-(−)-3-hydroxytetrahydrofuran (46 μL),0.57 mmol) to give Example 228 as a clear oil (27 mg, 37%).

[0812]¹H-NMR (400 HMz, CDCl₃) δ: 6.82 (m, 2H), 6.78 (m, 1H), 4.95 (m,1H), 4.03-3.20 (m, 10H), 3.82 (s, 3H), 3.66 (s, 3H), 2.17 (m, 2H), 1.17(t, 3H), 0.73 (s, 3H). LRMS (Electrospray, positive): Da/e 380.3 (m+1).

EXAMPLE 229 R¹=CH₂CH₂O-4-FPh; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-{3-[2-(4-fluorophenoxy)ethoxy]-4-methoxyphenyl}-3-methylpyrrolidinecarboxylate

[0813] Prepared by the K₂CO₃ etherification procedure of Example 43using Intermediate 74 (21.2 mg, 0.0685 mmol, 1 eq) and4-fluorophenoxyethyl bromide (60 mg, 0.27 mmol, 4.0 eq), yielding aclear, colorless oil (15.2 mg, 49.7%).

[0814]¹H NMR (400 HMz, CDC₃) δ: 6.99-6.83 (c, 7H), 4.35 (t, 2H), 4.29(t, 2H), 3.83 (s, 3H), 3.72 (s, 3H), 3.83-3.48 (c, 4H), 3.25 (dd, 1H),1.64 (s, 1H), 1.42 (br d, 1H), 1.13 (t, 3H), 0.73(s, 3H).

EXAMPLE 230 R¹=CH₂CH₂CH₂O-4-FPh; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenoxy)propoxy]-4-methoxyphenyl}-3-methylpyrrolidinecarboxylate

[0815] Prepared from Intermediate 74 (25.2 mg, 0.0815 mmol, 1 eq) by theK₂CO₃ etherification procedure of Example 43 using1-(3-chloropropoxy)-4-fluorobenzene (62 mg, 0.33 mmol, 4.0 eq) to yieldExample 230 as a clear, colorless oil (19.0 mg, 50.5%).

[0816]¹H NMR (400 HMz, CDCl₃) δ: 6.97-6.80 (c, 7H), 4.19 (m, 2H), 4.13(t, 2H), 3.82 (s, 3H), 3.72 (s, 3H), 3.83-3.48 (c, 4H), 3.25 (dd, 1H),2.27 (quintet, 2H), 1.70 (s, 1H), 1.56 (br d, 1H), 1.13 (t, 3H) 0.73(s,3H).

EXAMPLE 231 R¹=CH₂C≡CH; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(4-methoxy-3-prop-2-ynyloxyphenyl)-3-methylpyrrolidinecarboxylate

[0817] Prepared from Intermediate 74 via the K₂CO₃ etherificationprocedure of Example 43 using propargyl bromide.

[0818]¹H NMR (400 HMz, CDCl₃) δ: 6.97 (s, 1H), 6.87-6.82 (m, 2H), 4.76(s, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 3.90-3.55 (m, 5H), 3.27 (dd, 1H),2.48 (s, 1H) 1.49-1.46 (m, 1H), 1.14 (t, 3H), 0.75 (s, 3H). LRMS(Electrospray, positive): Da/e 348.1 (m+1).

EXAMPLE 232 R¹=CH₂C≡CCH₃; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-but-2-ynyloxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylate

[0819] Prepared from Intermediate 74 via the K₂CO₃ etherificationprocedure of Example 43 using 1-bromo-2-butyne.

[0820]¹H NMR (400 HMz, CDCl₃) δ: 6.96 (s, 1H), 6.85-6.82 (m, 2H),4.72-4.71 (m, 2H), 3.86 (s, 3H), 3.72 (s, 3H), 3.90-3.55 (m, 5H), 3.27(dd, 1H), 2.48 (s, 1H), 1.81 (s, 3H), 1.52-1.48 (m, 1H), 1.14 (t, 3H),0.77 (s,3H). LRMS (Electrospray, positive): Da/e 362.2 (m+1).

EXAMPLE 233 R¹=CH₂C≡CPh; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinecarboxylate

[0821] Prepared from Intermediate 74 by the Mitsunobu reaction ofExample 144 using 3-phenyl-2-propyn-1-ol.

[0822]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.41-7.38 (m, 2H),7.32-7.27 (m, 3H), 7.07 (d, 1H), 6.84 (s, 2H), 5.00-4.94 (m, 2H), 3.88(s, 3H), 3.72 (s, 3H), 3.80-3.69 (m, 3H), 3.57-3.50 (m, 2H), 3.23 (dd,1H), 1.35-1.32 (m, 1H), 0.98-0.94 (dd, 3H), 0.70(d, 3H). LRMS(Electrospray, positive): Da/e 424.2 (m+1).

EXAMPLE 234 R¹=CH₂C≡C-4-FPh; R³=CO₂CH₃ Methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinecarboxylate

[0823] Prepared from Intermediate 74 via the solid phase Mitsunobuprocedure of Example 144 using. Intermediate 89.

[0824]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.40-7.36 (m, 2H),7.04-6.97 (m, 3H), 6.85 (s, 2H), 4.97 (s, 2H), 3.88 (s, 3H), 3.72 (s,3H), 3.86-3.65 (m, 3H), 3.58-3.48 (m, 2H), 3.24 (dd, 1H), 1.013 (t, 3H),1.14 (t, 3H), 0.71 (d, 3H). LRMS (Electrospray, positive) Da/e 442.5(m+1).

EXAMPLE 235 R¹=CH₂C≡CPh; R³=COCH₂SAc1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-acetylthioethan-1-one

[0825] Prepared from Example 118 (30 mg, 0.082 mmol, 1.0 eq) by theCs₂CO₃ procedure of Example 176 using phenylpropargyl mesylate (17.4 mg,0.082 mmol, 1.0 eq, yielding a clear, colorless oil (13.2 mg, 33%).

[0826]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.45-6.86 (m, 8H),4.13-3.49 (c, 12H), 2.31 (s, 3H), 1.60 (s, 1H), 1.28-1.24 (dd, 1H),1.15-1.08 (dd, 3H), 0.73 (s, 3H)

EXAMPLE 236 R¹=CH₂C≡CPh; R³=COCH₂SH1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-sulfanylethan-1-one

[0827] Prepared from Example 235 (13.2 mg, 0.0274 mmol) by the LiOHhydrolysis procedure of Intermediate 5 to give a clear, colorless oil(10.5 mg, 87%).

[0828]¹H NMR (CD₃OH, 400 HMz, mixture of rotomers) δ: 7.41-7.20 (m, 5H),6.91-6.75(m, 3H), 4.01-3.29 (c, 12H), 3.21 (s, 1H), 1.88 (s, 1H),1.38-1.21 (m, 1H), 1.07-1.03 (m, 3H), 0.73-0.72 (m, 3H). LRMS(Electrospray, positive): Da/e 440.4 (m+1).

Intermediate 93{2-[(3S,4S)-3-((R)-1-Hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidin-1-yl]-2-oxo-ethyl)carbamicacid tert-butyl ester

[0829] To a flask containing a solution of Intermediate 70 (67.2 mg,0.27 mmol) in dioxane (2.0 mL) was added a 1.0 M solution of aqueousK₂CO₃ (1.0 mL, 1.0 mmol). A solution of N-Boc-glycine p-nitrophenylester (236 mg, 0.79 mmol) in dioxane (100 mL) was added via syringe tothe mixture. The mixture was stirred at room temperature for 30 minutes.The reaction was diluted with EtOAc (100 mL), then washed with aqueousNaHCO₃ (3×50 mL) and with brine (50 mL), dried over Na₂SO₄, filtered,and concentrated in vacuo to yield a yellow powder (43 mg. 84% yield).

[0830]¹H NMR (CDCl₃, 300 HMz, mixture of rotamers) δ: 6.88-6.77 (m, 2H,aromatic), 6.75-6.65 (m, 1H, aromatic), 5.56 (br, s, 1H, NH), 4.07-3.83(m, 3H), 3.89 (s, 3H, OMe), 3.82-3.68 (m, 2H), 3.67-3.52 (m, 2H), 3.46(d, 1H, J=11.5 Hz), 3.19 (d, 1H, J=11.5 Hz), 1.46 (s, 9H), 1.16-1.05 (m,3H), 0.74 (d, 3H). LRMS (Electrospray, positive): Da/e 353.151 (m+1).

EXAMPLE 2372-Amino-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoromethylphenyl)-prop-2-ynyloxy]phenyl}-3-methylpyrrolidin-1-yl)ethanone

[0831] Prepared from Intermediate 93 by the Cs₂CO₃ method of Example 176from the procedure of Example 109 to provide the product as an amber oil(12.7 mg, 4.1% yield).

[0832]¹H NMR (CDCl₃, 300 HMz, mixture of rotomers) δ: 7.55-7.4 (m, 4H,aromatic), 7.93 (s, 1H, aromatic), 6.85-6.7 (m, 2H, aromatic), 4.96 (s,2H), 4.38 (br. s, 2H), 4.0-3.4 (m, 7H), 3.83 (d, 3H, OMe), 3.2 (dd, 1H),1.0-0.88 (m, 3H), 0.65 (m, 3H). LRMS (Electrospray, positive): Da/e491.20 (m+1).

EXAMPLE 238 R¹=t-Bu; R³=COCO₂CH₃ Methyl2-{3-((1R)-1-hydroxyethyl)(3S,4S)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoacetate

[0833] Prepared from Intermediate 73 via the Hunig's base couplingprocedure of Intermediate 74 using methyl oxalyl chloride.

[0834]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 6.93-6.81 (m, 3H),4.01-3.44 (c, 12H), 1.32 (s, 9H), 1.16-1.12 (dd, 3H), 0.77-0.74 (d, 3H).LRMS (Electrospray, positive): Da/e 394.0 (m+1).

EXAMPLE 239 R¹=H; R³=COCO₂CH₃ Methyl2-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoacetate

[0835] Prepared from Example 238 via the TFA deprotection method ofExample 143.

[0836]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 6.85-6.70 (m, 3H),5.60-5.56 (br m, 1H), 4.00-3.46 (c, 12H), 1.17-1.13 (dd, 3H), 0.79-0.76(d and d, 3H). LRMS (Electrospray, positive): Da/e 338.1 (m+1).

EXAMPLE 240 R¹=CH₂C≡CPh; R³=COCO₂CH₃ Methyl2-{3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-oxoacetate

[0837] Prepared from Example 239 via the Mitsunobu method of Example 144using 3-phenyl-2-propyn-1-ol.

[0838]¹H NMR (400 HMz, CDCl₃, mixture of rotomers) δ: 7.41-7.26 (m, 5H),7.07 (s, 1H), 6.86-6.85 (m, 2H) 5.05-4.95 (m, 2H), 4.06-3.43 (c, 12H),0.98-0.91 (dd, 3H), 0.74-0.71 (d, 3H) LRMS (Electrospray, positive):Da/e 452.7 (m+1).

Intermediate 941-Benzyl-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-methyl-3-vinylpyrrolidine

[0839] A round bottom flask equipped with a stir bar and rubber septumwas charged with dry diethyl ether (10 mL) andmethyltriphenylphosphonium bromide (1.88 g, 5.27 mmol) under a nitrogenatmosphere. Butyllithium (2.32 mL, 5.80 mmol, 2.5 M in hexanes) then wasadded by syringe resulting in an orange/yellow suspension that wasstirred at room temperature for 3 hours. A Et₂O solution of Intermediate65 (2.0 g, 5.27 mmol in 10 mL of ether) then was added, discharging thecolor immediately. After stirring at room temperature for two hours, thereaction mixture was quenched with saturated NH₄Cl solution, extractedwith EtOAc (2×50 mL), dried (Na₂SO₄), and concentrated. Columnchromatography (Biotage system, 40M cartridge, 25% EtOAc/hexane)afforded 850 mg (43%) of an orange oil).

[0840]¹H NMR (400 HMz, CDCl₃) δ: 7.42-7.23 (m, 5H), 6.80-6.68 (m, 3H),6.05 (dd, 1H), 4.95 (dd, 1H), 4.87 (dd, 1H), 4.87 (dd, 1H), 3.86-3.79(m, 6H), 3.71 (dd, 2H), 3.22 (t, 1H), 3.04-2.96 (m, 2H), 2.81 (d, 1H),2.52 (d, 1H), 1.37-1.26 (m, 1H), 0.77 (s, 3H), 0.66-0.60 (m, 2H),0.37-0.32 (m, 2H).

Intermediate 954-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-methyl-3-vinylpyrrolidine-1-carboxylicacid methyl ester

[0841] A solution of Intermediate 94 (480 mg, 1.27 mmol) in 10 mL ofacetonitrile was treated with methyl chloroformate (491 μL, 6.36 mmol),and the mixture was refluxed for 6 hours. The reaction mixture then wasconcentrated under reduced pressure, and the residue purified bychromatography (Biotage system, 40s cartridge, 10% EtOAc/hexane to 20%EtOAc/hexane) to give 237 mg of a yellow oil (54%).

[0842]¹H NMR (400 HMz, CDCl₃) δ: 6.81 (d, 1H), 6.72-6.67 (m, 2H), 5.87(dd, 1H), 5.09 (d, 1H), 4.95 (dd, 1H), 3.85 (s, 3H), 3.84-3.68 (m, 7H),3.52-3.32 (m, 2H), 3.14 (t, 1H), 1.35-1.25 (m, 1H), 0.35 (s, 3H),0.66-0.60 (m, 2H), 0.37-0.32 (m, 2H).

EXAMPLE 241 R¹=CH₂C₃H₅; R³=CO₂CH₃; R₄=H; R₅=CH₂OH; R₆=H4-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(1,2-dihydroxyethyl)-3-methylpyrrolidine-1-carboxylicacid methyl ester

[0843] A reaction vial equipped with a stir vane was charged withIntermediate 95 (46 mg, 0.133 mmol), acetone (250 ul), water (500 ul),and N-methyl morpholine N-oxide (17.1 mg, 0.146 mmol). To this mixturewas added osmium tetroxide in t-butanol (50 μ, 0.004 mmol, 2.5 wt %solution). The resulting mixture was stirred at room temperature for 24hours. The reaction mixture then was diluted with 10% aqueous sodiumthiosulfate solution (5 mL), filtered through GF/F filter paper. Thefiltrate was extracted with EtOAc (2×10 mL), dried (Na₂SO₄), andconcentrated. Biotage purification (12S cartridge, 1:1:0.1EtOAc/hexane/MeOH) afforded 18 mg of Example 241 (36%).

[0844]¹H NMR (400 HMz, CDCl₃) δ: 6.81 (d, 1H), 3.86 (s, 3H), 3.85-3.36(c, 15H), 3.23 (dd, 1H), 1.35-1.27 (m, 1H), 0.75 (s, 3H), 0.66-0.59 (m,2H), 0.38-0.32 (m, 2H). LRMS (Electrospray, positive): Da/e 380.2 (m+1).

EXAMPLE 242 R¹=CH₂C₃H₅; R³=(S)—COCH(CH₂OC(CH₃)(CH₃)O)[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-(2,2-dimethyl-[1,3]dioxolan-4-(S)-yl)methanone

[0845] Intermediate 67 was acylated by the Hunig's base procedure ofIntermediate 74 using 2,2-dimethyl-[1,3]dioxolane-4-(S)-carbonylchloride to afford Example 242 (22%).

[0846]¹H NMR (CDCl₃, 400 HMz) δ: 6.83-6.78, m, 4H), 4.71-4.65 (m, 1H),4.37-4.32 (m, 1H), 4.23-4.15 (m, 1H), 3.95-3.44 (m, 10H), 1.72-1.15 (m,10H), 0.76 (s, 3H), 0.67-0.62 (m, 2H), 0.38-0.33 (m, 2H). LRMS(Electrospray, positive): Da/e 434.4 (m+1).

EXAMPLE 243 R¹=CH₂C₃H₅; R³=(S)—COCH(OH)CH₂OH1-[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-(S)-3-dihydroxypropan-1-one

[0847] Example 242 (9 mg, 20 μmol) was dissolved in a solution of aceticacid/water (3:1, 0.9 mL). The reaction mixture was stirred at roomtemperature for 72 hours. The solution was neutralized by pouring intoan NaHCO₃ solution. The solution was concentrated to dryness, then thesolids were extracted five times with CH₂Cl₂. The combined organics weredried over Na₂SO₄ and concentrated in vacuo (5.1 mg, 62%).

[0848]¹H NMR (CDCl₃, 400 HMz) δ: 6.84-6.76,m, 3H), 4.40-4.37 (m, 1H),3.89-3.32 (m, 11H), 2.33-1.95 (m, 1H), 1.34-1.12 (m, 7H), 0.89-0.81 (m,1H), 0.78-0.73 (m, 3H), 0.66-0.61 (m, 2H), 0.37-0.32 (m, 2H). LRMS(Electrospray, positive): Da/e 394.0 (m+1).

EXAMPLE 244 R¹=2-indanyl; R³=(R)—COCH(OH)CH₂OH(R)-2,3-Dihydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[3-(indan-2-ylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidin-1-yl}propan-1-one

[0849] Prepared from Intermediate 96 by the procedure described inExample 75 and deprotected as in Example 243.

[0850]¹H NMR (CDCl₃, 300 HMz, mixture of rotomers) δ: 7.26-7.16 (m, 4H,aromatic), 6.83-6.82 (br. s, 3H, aromatic), 5.19-5.15 (m, 1H), 4.45-4.32(m, 1H), 4.10-3.50 (m, 8H), 3.80 (d, 3H, OMe), 3.45-3.12 (m, 5H),1.27-1.25 (m, 1H), 1.20-1.15 (m, 3H), 0.79-0.77 (m, 3H). LRMS(Electrospray, positive): Da/e 470.58 (m+1)

EXAMPLE 245 R¹=4-F—Ph—OCH₂CH₂CH₂; R³=(R)—COCH(OH)CH₂OH)(S)-1-[(3S,4S)-4-(3-[3-(4-Fluorophenoxy)propoxy]-4-methoxyphenyl}-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2,3-dihydroxypropan-1-one

[0851] Prepared by the procedure set forth in Example 243.

[0852]¹H NMR (CDCl₃, 300 HMz, mixture of rotomers) δ: 6.99-6.92 (m, 2H,aromatic), 6.87-6.79 (m, 5H, aromatic), 4.39 (s, 1H), 4.22-4.12 (m, 4H),4.0 (d, 1H), 3.89-3.56 (m, 7H), 3.83 (s, 3H, OMe), 3.4-3.32 (dd, 1H),2.32-2.24 (m, 2H) 1.17-1.12 (m, 3H), 0.74 (d, 3H). LRMS (Electrospray,positive): Da/e 492.25 (m+1).

Intermediate 961-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-[(3S,4S)-3-((R)-1-hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidin-1-yl)methanone

[0853] A round bottom flask equipped with a stir bar and rubber septumwas charged with5-[4-(1-hydroxy-ethyl)-4-methylpyrrolidin-3-yl)-2-methoxyphenol (2.4 g,9.55 mmol), dry CH₂Cl₂ (50 mls), and DIEA (3.49 mls, 20.1 mmol) under anitrogen atmosphere. The mixture was chilled to 0° C. and(S)-2.2-dimethyl-[1,3]dioxolane-4-carbonyl chloride (3.14 g, 19.1 mmol)in 15 ml of CH₂Cl₂ was added dropwise by syringe. The reaction mixturewas allowed to gradually warm to room temperature over a 16-hour period.The mixture then was diluted with 50 ml of CH₂Cl₂, washed with 1N HCl(2×50 ml), saturated aqueous NaHCO₃ (1×50 ml), dried over Na₂SO₄, andconcentrated to 3.9 g of a tan foam. The material was taken up in 100 mlCH₃OH and chilled to 0° C. Three equivalents of aqueous 1N LiOH thenwere added (29 ml, 29.0 mmol), the mixture was stirred at 0° C. for 2hours, then warmed to room temperature for 2 hours. The reaction mixturenext was concentrated under reduced pressure with the bath temperatureat 30° C. to remove CH₃OH. The remaining aqueous material wasneutralized with saturated NH₄Cl to pH 7 and extracted with EtOAc (2×100ml). The extracts were dried over Na₂SO₄ and concentrated to 2.74 g of atan foam (76%).

[0854]¹H NMR (CDCl₃, 400 HMz, mixture of rotomers) δ: 6.90-6.70 (m, 3H),5.66 (br, s, 1H), 4.68 (t, 1H), 4.34 (t, 1H), 4.23-4.09 (m, 6H), 3.89(s, 3H), 3.94-3.42 (m, 5H), 1.49-1.37 (m, 6H), 1.17 (d, 3H), 0.76 (s,3H). LRMS (Electrospray, positive): Da/e 378.3 (m−1).

EXAMPLE 246 R¹=F₃C—Ph—C≡CCH₂; R³=CO-2,2-dimethyl-1,3-dioxolan-4-yl1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoro-methylphenyl)prop-2-ynyloxy]phenyl}-3-methylpyrrolidin-1-yl)methanone

[0855] To a flask containing anhydrous Cs₂CO₃ (67 mg, 0.206 mmol, 1.1eq) under a nitrogen blanket was added a solution of Intermediate 96 (71mg, 0.187 mmol, 1.0 eq) in anhydrous acetone (1 mL). Intermediate 92(52.1 mg, 0.187 mmol, 1.0 eq) was added to the mixture via syringe. Thereaction mixture then was heated and stirred at 65° C. for 4 hours. Thereaction mixture was cooled to room temperature and diluted with water(50 mL). The aqueous solution was extracted with EtOAc (3×30 mL), andthe combined organics were washed with brine (50 mL), then dried overNa₂SO₄, filtered, and concentrated in vacuo to yield a white foamyproduct (104 mg).

[0856]¹H NMR (CDCl₃, 300 HMz, mixture of rotomers) δ: 7.5-7.35 (m, 4H,aromatic), 6.96 (d, 1H, aromatic), 6.85-6.75 (m, 2H, aromatic), 4.92 (d,2H, CH₂), 4.65-4.50 (m, 1H), 4.35-4.20 (m, 1H), 4.15-4.00 (m, 1H),3.85-3.40(m, 5H), 3.8 (d, 3H, OMe), 3.35-3.30 (dd, 1H), 1.45-1.25 (2d,6H, Me), 1.0-0.9(m, 3H), 0.63 (d, 3H). LRMS (Electrospray, positive):Da/e 562.25 (m+1).

EXAMPLE 247 R¹=F₃C—Ph—C≡—CCH₂; R³=CO—CH(OH)CH₂OH(R)-2,3-Dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoromethylphenyl)prop-2-ynyloxy]phenyl}-3-methylpyrrolidin-1-yl)propan-1-one

[0857] To a reaction vial containing Example 246 (104 mg, 0.185 mmol)was added acetic acid (3.0 mL) and water (1.0 mL). The vial then wassealed, heated to 50° C., and stirred for 2 hours. The reaction mixturewas concentrated in vacuo and purified by reversed-phase HPLC on a C18column (Luna 10: C18, 250×10 mm). Gradient elution of 50-100%acetonitrile-water (0.05% TFA) yielded product as amber oil (27.8 mg,28.5% yield).

[0858]¹H NMR (CDCl₃, 300 HMz, mixture of rotomers) δ: 7.6-7.45 (m, 4H,aromatic), 7.69 (d, 1H, aromatic), 6.9-6.82 (m, 2H, aromatic), 5.0 (m,2H), 4.4-4.32 (m, 1H), 4.1-3.2 (m, 7H), 3.89 (d, 3H, OMe), 1.05 (s, 3H),0.72 (m, 3H). LRMS (Electrospray, positive): Da/e 522.15 (m+1).

EXAMPLE 248 R¹=3-thienyl-CH₂CH₂; R³=COCH₂OCH₂Ph2-Benzyloxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(2-thiophen-3-yl-ethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

[0859] Prepared by alkylation of Example 143 by the K₂CO₃ procedure ofExample 7 using 2-(3-thienyl)ethyl bromide.

[0860]¹H NMR data δ: 7.27-7.38 (m, 6H); 7.05-7.07 (m, 1H); 7.12-7.13 (m,1H); 6.74-6.84 (m, 3H); 6.05 (s, 2H); 4.15-4.22 (m, 4H); 3.44-3.93 (m,6.5H); 3.86 (s, 3H); 3.14-3.24 (m, 2.5H); 1.13 (dd, 3H); 0.72 (s, 3H).

EXAMPLE 249 R¹=Ph(cyclo-C₃H₄)CH₂; R³=COCH₂OH2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-((R)-2-phenylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

[0861] Prepared by alkylation of Example 143 by the Mitsunobu procedureof Example 144 using 2-phenylcyclopropanol and removal of the benzylgroup by the debenzylation procedure of Intermediate 31.

[0862]¹H NMR data δ: 7.17-7.30 (m, 5H); 6.72-6.85 (m, 3H); 4.00-4.14 (m,2H); 3.49-3.98 (m, 8.5H); 3.86 (s, 3H); 3.05 (d, 0.5H): 2.86-2.93 (m,1H); 2.51-2.60 (m, 1H); 2.27-2.34 (m, 1H); 1.02-1.05 (dd, 3H); 0.74 (sd,3H).

EXAMPLE 250 R¹=C₅H₉CH₂CH₂CH₂; R³=COCH₂OH1-[(3S,4S)-4-[3-(3-Cyclopentylpropoxy)-4-methoxyphenyl]-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone

[0863] Prepared from Example 143 by the Mitsunobu procedure of Example144 using 3-cyclopentylpropan-1-ol and removal of the benzyl group bythe debenzylation procedure of Intermediate 31.

[0864]¹H NMR data δ: 6.75-6.83 (m, 3H); 4.12-4.15 (m, 2H); 3.96-4.01 (m,2.5H); 3.86 (s, 3H); 3.79-3.86 (m, 1H); 3.59-3.70 (m, 4H); 3.06 (d,0.5H); 1.75-1.88 (m, 5H); 1.44-1.61 (m, 6H); 1.16 (t, 5H); 0.77 (sd,3H).

EXAMPLE 251 R¹=PhCH₂CH₂CH₂; R³=COCH₂OH2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylpropoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

[0865] Prepared from Example 143 by the K₂CO₃ procedure of Example 7using 3-phenylpropyl chloride and removal of the benzyl group by thedebenzylation procedure by Intermediate 31.

[0866]¹H NMR data δ: 7.16-7.31 (m, 5H); 6.74-6.85 (m, 3H); 4.13-4.15 (m,2H); 3.94-4.04 (m, 2H); 3.86 (s, 3H); 3.76-3.83 (m, 1H); 3.47-3.70 (m,4H); 3.04-3.07 (m, 3H); 2.80-2.85 (t, 2H); 2.10-2.20 (quint, 2H); 1.14(t, 3H); 0.74 (s, 3H).

EXAMPLE 252 R¹=1-hydroxyindan-2-yl; R³=COCH₂OH2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[3-(1-hydroxyindan-2-yloxy)-4-methoxyphenyl]-3-methylpyrrolidin-1-yl}ethanone

[0867] Prepared from Example 143 by the K₂CO₃ procedure of Example 7using indene oxide and removal of the benzyl group by the debenzylationprocedure of Intermediate 31.

[0868]¹H NMR data δ: 7.48-7.51 (m, 1H); 7.24-7.32 (m, 3H); 6.85-6.96 (m,3H); 5.11-5.14 (m, 1H); 4.84-4.89 (m, 1H); 3.98-4.15 (m, 3H); 3.84-3.86(m, 1H); 3.83 (s, 3H); 3.50-3.78 (m, 4.5H); 3.16-3.32 (m, 2H); 3.06 (d,0.5H); 1.15-1.20 (m, 3H); 0.77 (s, 3H).

EXAMPLE 253 R¹=4-CH₃OPhCH₂CH₂; R³=COCH₂OH2-Hydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[2-(4-methoxyphenyl)ethoxy]phenyl}-3-methylpyrrolidin-1-yl)ethanone

[0869] Prepared from Example 143 by the K₂CO₃ procedure of Example 7using 1-(2-chloroethyl)-4-methoxybenzene and removal of the benzyl groupby the debenzylation procedure of Intermediate 31.

[0870]¹H NMR data δ: 7.20-7.23 (d, 2H); 6.74-6.88 (m, 5H); 4.10-4.18 (m,4H); 3.72-3.91 (m, 2H); 3.86 (s, 3H); 3.80 (s, 3H); 3.48-3.64 (m, 4H);3.02-3.11 (m, 2H); 1.12-1.17 (m, 3H); 0.74 (s, 3H).

EXAMPLE 254 R¹=CH₃(cyclo-C₃H₄)CH₂; R³=COCH₂OH2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-((R)-2-methylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone

[0871] Prepared from Example 143 by the K₂CO₃ procedure of Example 7using 1-(2-chloroethyl)-4-methoxybenzene and removal of the benzyl groupby the debenzylation procedure of Intermediate 31.

[0872]¹H NMR data δ: 6.77-6.84 (m, 3H); 4.15-4.18 (m, 2H); 3.78-3.99 (m,4H); 3.86 (s, 3H); 3.49-3.71 (m, 3.5H); 3.08 (d, 0.5H); 1.14-1.19 (m,3H); 1.07 (sd, 3H); 0.92-1.03 (m, 1H); 0.76-0.77 (m, 4H); 0.50-0.52 (m,1H); 0.37-0.41 (m, 1H).

EXAMPLE 2551-(R)-[1-(2-Benzyloxyethyl)-4-(S)-(3-cyclopentyloxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]-ethanol

[0873] Intermediate 68 (86.4 mg, 0.27 mmol) was dissolved in1,2-dichloroethane (1 mL) and the solution was treated withbenzyloxyacetaldehyde (38 μL, 0.27 mmol), followed by sodiumtriacetoxyborohydride (81 mg, 0.38 mmol). The reaction was stirred for18 hours at room temperature. Additional sodium triacetoxyborohydride(40 mg, 0.19 mmol) was added and stirring continued for 8 hours. Thereaction mixture was diluted with 1.0 M NaOH (0.5 mL) and stirredvigorously for 15 minutes. The layers were separated, the aqueous phasewas washed with CH₂Cl₂, and the organic layers were combined. Afterwashing with 6% NaHCO₃, the organics were dried with Na₂SO₄, thenconcentrated in vacuo. The crude material (129 mg) was chromatographedon silica gel with CHCl₃/95% ethanol/conc. NH₄OH (170:15:1), providingExample 255 (27 mg, 22%).

[0874]¹H NMR (CDCl₃, 400 HMz) δ: 7.36-7.26 (m, 5H), 6.81-6.73 (m, 3H),4.79-4.73 (m, 1H), 4.54 (s, 1H), 3.82 (s, 3H), 3.71-3.54 (m, 4H),3.40-3.35 (m, 1H), 3.24-3.21 (m, 1H), 2.80-2.67 (m, 2H), 2.63-2.56 (m,1H), 2.16-2.09 (m, 1H), 1.95-1.88 (m, 8H), 1.65-1.57 (m, 2H), 1.22-1.10(m, 3H), 0.49 (m, 3H). LRMS (Electrospray, positive): 454.5 Da/e (m+1).

EXAMPLE 2561-(R)-[4-(S)-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-hydroxyethyl)-3-(S)-methylpyrrolidin-3-yl]ethanol

[0875] Example 255 (25 mg, 55 mmol) was subjected to the debenzylationprocedure of Intermediate 31 to afford Example 256 (7.4 mg, 28%) as theTFA salt after HPLC purification.

[0876]¹H NMR (CDCl₃, 400 HMz) δ: 6.84-6.65 (m, 3H), 5.40-4.90 (brd, 2H),4.74 (brd s, 1H), 4.26-3.21 (m, 11H), 1.97-1.73 (m, 6H), 1.66-1.56 (m,3H), 1.33-0.77 (m, 4H), 0.69 (s, 3H). LRMS (Electrospray, positive):364.4 Da/e (m+1).

EXAMPLE 2572-Benzyloxy-1-[4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-hydroxymethyl-3-methylpyrrolidin-1-yl]ethanone

[0877][4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]methanol(100 mg, 0.34 mmol) was dissolved in CH₂C₂ (1.7 mL), and the solutionwas cooled to 0° C. DIEA (144 μL, 0.82 mmol) was added, followed bybenzyloxyacetyl chloride (114 μL, 0.72 mmol). The reaction was allowedto warm to room temperature slowly and stirred for 18 hours. Water wasadded (0.25 mL) and the reaction was stirred for 1.5 hours. CH₂C₂ wasadded and the mixture was washed once with water, twice with 1N HCl,once with water, twice with 6% NaHCO₃, then dried over Na₂SO₄ andconcentrated in vacuo. The residue was dissolved in THF (1 mL) andcooled to 0° C. A solution of LiOH in water (1.36M, 1 mL, 1.36 mmol) wasadded and the hydrolysis was allowed to proceed at 0° C. for 4 hours.The reaction mixture was quenched with saturated NH₄Cl, and the THF wasremoved by concentration in vacuo. The residue was resuspended in CH₂C₂,and washed twice with 6%. NaHCO₃, dried over Na₂SO₄ and concentrated invacuo.

[0878]¹H NMR (CDCl₃, 400 HMz) δ: 7.40-7.28 (m, 5H), 6.83-6.79 (m, 1H),6.73-6.66 (m, 2H), 4.66 (s, 2H), 4.16-4.13 (m, 2H), 3.86 (s, 3H),3.83-3.78 (m, 3H), 3.63-3.26 (brd m, 4H), 3.06-3.00 (m, 1H), 2.50-2.45(brd m, 1H), 1.34-1.12 (m, 1H), 1.03-0.99 (m, 2H), 0.73 (s, 3H),0.66-0.61 (m, 2H), 0.36-0.32 (m, 2H) LRMS (Electrospray, positive): Da/e440.3 (m+1).

Intermediate 97[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]methanol

[0879] Intermediate 65 (0.99 g, 2.6 mmol) was dissolved in ethanol (95%,10 mL) and the solution was treated with Pearlman's catalyst (20%Pd(OH)₂ on carbon, 250 mg). The mixture was hydrogenated at 1 atmosphereof H₂ for 16 hours. Additional catalyst (250 mg) was added and thereaction continued for an additional 24 hours. The catalyst was removedby filtration and the reaction mixture was concentrated in vacuo (0.68g, 89%).

[0880]¹H NMR (CDCl₃, 400 HMz) δ: 6.84-6.73 (m, 3H), 3.87-3.83 (m, 4H),3.59-3.47 (m, 3H), 3.30-3.20 (m, 3H), 2.85 (d, J=10.6, 1H), 2.35-2.12(brd m, 1H), 1.35-1.27 (m, 1H), 0.64-0.60 (m, 4H), 0.37-0.31 (m, 2H),0.36-0.32 (m, 2H). LRMS (Electrospray, positive): Da/e 377.3 (m+1).

EXAMPLE 2581-(2-Benzyloxyacetyl)-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidine-3-carbaldehyde

[0881] Oxalyl chloride (2.0 M in CH₂Cl₂, 0.175 mL, 0.35 mmol) was addedto CH₂Cl₂ (0.52 mL). The resulting solution was cooled to −60° C. Asolution of DMSO (47 mL, 0.66 mmol) dissolved in CH₂Cl₂ (0.18 mL) thenwas added dropwise. The solution was stirred for 5 minutes and Example257 (dissolved in 1.0 mL CH₂Cl₂) added to a Swern oxidation mixture.After the reaction had been stirred for 30 minutes at −60° C., Et₃N(0.25 mL) was added and the reaction mixture was warmed to roomtemperature. After 30 minutes, water was added and the solution wasstirred vigorously for 15 minutes. The layers were separated, theaqueous phase washed once with CH₂Cl₂. The combined organic layers werewashed with saturated NaCl, dried over Na₂SO₄, and concentrated invacuo. The crude material was chromatographed on SiO₂ usingEtOAc/hexanes (2:1), (76 mg, 50%).

[0882]¹H NMR (CDCl₃, 400 HMz) δ: 9.62-9.57 (m, 1H), 7.41-7.30 (m, 5H),6.84-6.78 (m, 1H), 6.68-6.56 (m, 2H), 4.68-4.63 (m, 2H), 4.20-4.10 (m,2H), 4.05-3.32 (m, 5H), 3.87 (s, 3H), 1.57-1.55 (m, 2H), 1.33-1.24 (m,1H), 0.92-0.88 (m, 3H), 0.67-0.60 (m, 2H), 0.37-0.31 (m, 2H).

EXAMPLE 2591-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-[(3S,4S)-3-((R)-1-hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidin-1-yl]methanone

[0883]

[0884] To a stirred solution of Intermediate 70 (73.5 mg, 0.293 mmol,1.0 eq) in CH₂Cl₂ (3 mL) at room temperature under a nitrogen blanketwas added Et₃N (65.2 mg, 0.645 mmol), followed by2,2-dimethyl-1,3-dioxolane-(4R)-carbonyl chloride (53.2 mg, 0.322 mmol).The reaction was stirred at room temperature overnight. The reactionmixture then was poured into 50 mL EtOAc, washed with brine, dried withNa₂SO₄, and concentrated in vacuo to give a foamy product (94 mg, 85%yield). The crude product was hydrolyzed by LiOH via Intermediate 5 toyield Example 259.

[0885]¹H NMR (CDCl₃, 300 HMz) δ: 6.97-6.58 (m, 3H, aromatic), 4.68 (t,1H, J=6.4 Hz), 4.44-4.34 (m, 1H), 4.24-3.95 (m, 1H), 3.94-3.50 (m, 5H),3.87 (d, 3H, OMe), 3.42 (d, 1H, J=12.4 Hz), 3.35 (d, 1H, J=12.4 Hz), 1.4(m, 6H), 1.15 (m, 3H), 0.75 (m, 3H).

EXAMPLE 2601-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl-)-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}methanone

[0886]

[0887] Prepared from Example 259 (126 mg, 0.332 mmol, 1.0 eq) andIntermediate 90 (69.8 mg, 0.332 mmol, 1.0 eq) by the method of Example176 to yield a white foamy product (160 mg).

[0888]¹H NMR (CDCl₃, 300 HMz, mixture of rotamers) δ: 7.42-7.25 (m, 5H,aromatic), 7.08 (d, 1H, aromatic), 6.86 (d, 2H, aromatic), 5.0 (d, 2H,CH₂), 4.72-4.60 (m, 1H), 4.45-4.32 (m, 1H), 4.22-4.10 (m, 1H), 3.95-3.70(m, 3H), 3.89 (s, 3H, OMe), 3.70-3.45 (m, 2H), 3.44-3.29 (m, 1H),1.5-1.38 (2d, 6H, Me), 1.02-0.75-0.65(m, 3H), 0.63 (d, 3H). LRMS(Electrospray, positive): Da/e 494.55 (m+1).

EXAMPLE 261(R)-2,3-Dihydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}propan-1-one

[0889]

[0890] To a reaction vial containing Example 260 (160 mg, 0.323 mmol)was added acetic acid (3.0 mL) and water (1.0 mL). The vial was sealed,heated to 50° C., and stirred for 2 hours. The reaction was concentratedin vacuo and purified by reversed-phase HPLC on a C18 column (Luna 10μ,C18, 250×10 mm). Gradient elution of 50-100% acetonitrile-water (0.05%TFA) provided Example 261 as white foamy solid (52.2 mg, 35.6% yield).

[0891]¹H NMR (CDCl₃, 300 HMz, mixture of rotamers) δ: 7.5-7.21 (m, 5H,aromatic), 7.05 (m, 1H, aromatic), 6.9-6.75 (m, 2H, aromatic), 5.0 (d,2H), 4.31 (s, 1H), 4.01-3.2 (m, 9H), 3.88 (s, 3H, OMe), 1.01-0.9 (m, 253H), 0.7 (s, 3H). LRMS (Electrospray, positive): Da/e 454.20 (m+1).

EXAMPLE 2621-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-[(3S,4S)-3-((R)-1-hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidin-1-yl]methanone

[0892]

[0893] To a stirred solution of Intermediate 70 (73.5 mg, 0.293 mmol,1.0 eq) in CH₂Cl₂ (3 mL) at room temperature under a nitrogen blanketwas added Et₃N (65.2 mg, 0.645 mmol), followed by2,2-dimethyl-1,3-dioxolane-(4S)-carbonyl chloride (53.2 mg, 0.322 mmol).The reaction was stirred at room temperature overnight, then poured into50 mL EtoAc, washed with brine, dried with Na₂SO₄, and concentrated invacuo. to give a foamy product (94 mg, 85% yield). The crude product washydrolyzed by LiOH via Intermediate 5 to yield Example 262.

[0894]¹H NMR (CDCl₃, 300 HMz) δ: 6.93-6.65 (m, 3H, aromatic), 5.68 (s,1H), 4.67 (m, 1H), 4.34 (m, 1H), 4.21 (m, 1H), 3.94-3.40 (m, 5H), 3.89(s, 3H, OMe), 1.4 (m, 6H), 1.16 (m, 3H), 0.76 (m, 3H).

EXAMPLE 2631-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}methanone

[0895]

[0896] Prepared from Example 262 (126 mg, 0.332 mmol, 1.0 eq) andIntermediate 90 (69.8 mg, 0.332 mmol, 1.0 eq) by the method of Example176 to yield a white foamy product (160 mg,).

[0897]¹H NMR (CDCl₃, 300 HMz, mixture of rotamers) δ: 7.52-7.15 (m, 5H,aromatic), 7.08 (d, 1H, aromatic), 6.86 (d, 2H, aromatic), 5.98 (m, 2H,CH₂), 4.64 (m, 1H), 4.35-4.32 (m, 1H), 4.22-4.10 (m, 1H), 3.97-3.36 (m,5H), 3.89 (s, 3H, OMe), 1.5-1.38 (2d, 6H, Me), 1.02-0.75 (m, 3H), 0.74(s, 3H). LRMS (Electrospray, positive): Da/e 494.55 (m+1).

EXAMPLE 264(S)-2,3-Dihydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}propan-1-one

[0898]

[0899] To a reaction vial containing Example 263 (160 mg, 0.323 mmol)was added acetic acid (3.0 mL) and water (1.0 mL). The vial was sealed,heated to 50° C. and stirred for 2 hours. The reaction was concentratedin vacuo and purified by reversed-phase HPLC on a C18 column (Luna 10μ,C18, 250×10 mm). Gradient elution of 50-100% acetonitrile-water (0.05%TFA) gave product as white foamy solid (52.2 mg, 35.6% yield).

[0900]¹H NMR (CDCl₃, 300 HMz, mixture of rotamers) δ: 7.44-7.18 (m, 5H,aromatic), 7.08 (s, 1H, aromatic), 6.86 (s, 2H, aromatic), 4.6 (s, 2H,CH₂), 4.4-4.3 (m, 1H), 4.01-4.62 (m, 7H), 3.89 (s, 3H, OMe), 3.59-3.46(m, 1H), 3.32-3.29 (m, 1H), 2.4 (m, 1H), 0.95 (m, 3H), 0.72 (d, 3H).LRMS (Electrospray, positive): Da/e 454.20 (m+1). [α]_(D)=14.6° (c=1.00,EtOH).

EXAMPLE 265 R₁=t-Bu; R₃=(S)—COCH(OAc)CH₂Ph

[0901] Prepared from Intermediate 73 by acylation with acetic acid(S)-1-chlorocarbonyl-2-phenylethyl ester according to procedure of F.Babudri et al., Tetrahedron, 8, 2431-2440 (1999).

[0902] LRMS (Electrospray, positive): m/z 498 (m+1).

EXAMPLE 266 R₁=H; R₃=(S)—COCH(OAc)CH₂Ph

[0903] Prepared from Example 265 by the TFA method of Example 143 toafford Example 266.

[0904] LRMS (Electrospray, positive): m/z 442 (m+1).

EXAMPLE 267 Acetic acid(S)-1-benzyl-2-{(3S,4S)-3-((R)-1-hydroxy-ethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}-2-oxo-ethylester R¹=PhC≡CCH₂; R₃=(S)—COCH(OAc)CH₂Ph

[0905] Example 266 (88 mg, 0.2 mmol) and Intermediate 90 (50 mg, 0.24mmol) were subjected to the Cs₂CO₃ procedure of Example 176, and thecrude residue (110 mg) was used without further purification.

EXAMPLE 268(S)-2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}-3-phenylpropan-1-oneR¹=PhC≡CCH₂; R₃=(S)—COCH(OH)CH₂Ph

[0906] Example 267 (110 mg crude, 0.2 mmol theoretical) was subjected tothe O-Acetate deprotection procedure and purified by HPLC (20×50 mm YMCCombiPrep C18 column, 20 mL/min, 10-95% acetonitrile/water in 7 min) toyield Example 268 (38 mg, 75%).

[0907]¹H NMR (300 HMz, CDCl₃, mixture of rotamers) δ: 7.50-7.16 (m,10H), 7.10-6.52 (m, 3H), 5.05-4.92 (m, 2H), 4.52-4.36 (m, 1H), 3.88 (s,3H), 3.87-2.72 (m, 9H), 1.48/1.29 (2d, J=4.3/4.6 Hz, 1H), 0.93/0.88 (2d,J=6.4 Hz, 3H), 0.66/0.51 (2s, 3H). LRMS (Electrospray, positive): m/e514 (m+H)⁺.

[0908] The compounds of structural formula (II) were tested for anability to inhibit PDE4. The ability of a compound to inhibit PDE4activity is related to the IC₅₀ value for the compound, i.e., theconcentration of inhibitor required for 50% inhibition of enzymeactivity. The IC₅₀ value for compounds of structural formula (II) weredetermined using recombinant human PDE4.

[0909] The in vitro phosphodiesterase activity inhibitory IC₅₀ values,and the resulting calculated K_(i) values of compounds set forth in theexamples were determined by measuring the inhibition of cAMP hydrolysisas a function of the concentration of the test compound over the rangeof 0 to 1 mM. The K_(i) values of the compounds tested in theaforementioned assay ranged from about 0.0003 μM to about 100 μM.

[0910] The compounds of the present invention typically exhibit an IC₅₀value against recombinant human PDE4 of less than about 50 μM, andpreferably less than about 25 μM, and more preferably less than about 15μm. The compounds of the present invention typically exhibit an IC₅₀value against recombinant human PDE4 of less than about 1 μM, and oftenless than about 0.05 μM. To achieve the full advantage of the presentinvention, a present PDE4 inhibitor has an IC₅₀ of about 700 pM(picomolar) to about 15 μM.

[0911] The IC₅₀ values for the compounds were determined fromconcentration-response curves typically using concentrations rangingfrom 0.1 pM to 500 μM. Tests against other PDE enzymes using standardmethodology, as described in Loughney et al., J. Biol. Chem., 271, pp.796-806 (1996), also showed that compounds of the present invention arehighly selective for the cAMP-specific PDE4 enzyme.

[0912] In particular, a compound of the present invention, i.e., Sample66, has an IC₅₀ vs. human recombinant PDE4B of 0.015 μM, but has an IC₅₀vs. PDE1A of 80 μM, vs. PDE1B of 100 μM, vs. PDE1C of 12 μM, vs. PDE2 of450 μM, vs. PDE3A of 40 μM, vs. PDE5 of 270 μM, and vs. PDE7 of 36 μM.This illustrates the selectivity of the present compound with respect toinhibiting PDE4.

[0913] The compounds of structural formula (II) also were tested for anability to reduce TNFα secretion in human peripheral blood lymphocytes.The ability to reduce TNFα secretion is related to the EC₅₀ values(i.e., the effective concentration of the compound capable of inhibiting50% of the total TNFα).

[0914] The in situ inhibition of TNFα release derived from endotoxintreated isolated human peripheral blood lymphocytes resulted in EC₅₀values of compounds set forth in the examples were determined as afunction of the concentration of the test compound over a range of 0 to100 μM. The EC₅₀ values of the compounds tested in the aofrementionedassay ranged from about 0.0002 μM to about 20 μM.

[0915] The compounds of the present invention typically exhibit an EC₅₀value of less than about 50 μM, and preferably less than about 25 μM,and more preferably less than about 15 μM. The compounds of the presentinvention typically exhibit a PBL/TNFα EC₅₀ value of less than about 1μM, and often less than about 0.05 μM. To achieve the full advantage ofthe present invention, a present PDE4 inhibitor has an EC₅₀ value ofabout 1000 pM (picomolar) to about 20 μM.

[0916] The production of recombinant human PDEs and the IC₅₀ and EC₅₀determinations can be accomplished by well-known methods in the art.Exemplary methods are described as follows:

Expression of Human PDEs

[0917] Expression in Baculovirus-Infected Spodoptera fugiperda (Sf9)Cells

[0918] Baculovirus transfer plasmids were constructed using eitherpBlueBacIII (Invitrogen) or pFastBac (BRL-Gibco). The structure of allplasmids was verified by sequencing across the vector junctions and byfully sequencing all regions generated by PCR. Plasmid pBB-PDE1A3/6contained the complete open reading frame of PDE1A3 (Loughney et al., J.Biol. Chem., 271, pp. 796-806 (1996)) in pBlueBacIII. Plasmid Hcam3aBBcontained the complete open reading frame of PDE1C3 (Loughney et al.(1996)) in pBlueBacIII. Plasmid pBB-PDE3A contained the complete openreading frame of PDE3A (Meacci et al., Proc. Natl. Acad. Sci., USA, 89,pp. 3721-3725 (1992)) in pBlueBacIII.

[0919] Recombinant virus stocks were produced using either the MaxBacsystem (Invitrogen) or the FastBac system (Gibco-BRL) according to themanufacturer's protocols. In both cases, expression of recombinant humanPDEs in the resultant viruses was driven off the viral polyhedronpromoter. When using the MaxBac® system, virus was plaque purified twicein order to insure that no wild type (occ+) virus contaminated thepreparation. Protein expression was carried out as follows. Sf9 cellswere grown at 27° C. in Grace's Insect culture medium (Gibco-BRL)supplemented with 10% fetal bovine serum, 0.33% TC yeastolate, 0.33%lactalbumin hydrolysate, 4.2 mM NaHCO₃, 10 μg/mL gentamycin, 100units/mL penicillin, and 100 μg/mL streptomycin. Exponentially growingcells were infected at a multiplicity of approximately 2 to 3 virusparticles per cell and incubated for 48 hours. Cells were collected bycentrifugation, washed with nonsupplemented Grace's medium, andquick-frozen for storage.

[0920] Expression in Saccharomyces cerevisiae (Yeast)

[0921] Recombinant production of human PDE1B, PDE2, PDE4A, PDE4B, PDE4C,PDE4D, PDE5, and PDE7 was carried out similarly to that described inExample 7 of U.S. Pat. No. 5,702,936, incorporated herein by reference,except that the yeast transformation vector employed, which is derivedfrom the basic ADH2 plasmid described in Price et al., Methods inEnzymology, 185, pp. 308-318 (1990), incorporated yeast ADH2 promoterand terminator sequences and the Saccharomyces cerevisiae host was theprotease-deficient strain BJ2-54 deposited on Aug. 31, 1998 with theAmerican Type Culture Collection, Manassas, Va., under accession numberATCC 74465. Transformed host cells were grown in 2×SC-leu medium, pH6.2, with trace metals, and vitamins. After 24 hours, YEPmedium-containing glycerol was added to a final concentration of2×YET/3% glycerol. Approximately 24 hr later, cells were harvested,washed, and stored at −70° C.

Calmodulin Purification

[0922] Calmodulin used for activation of the PDE1 enzymes was purifiedfrom bovine testes essentially as described by Dedman et al., Methods inEnzymology, 102, pp. 1-8 (1983) using the Pharmacia Phenyl-Sepharose®procedure.

Immobilization of Calmodulin on Agarose

[0923] Calmodulin was immobilized on BioRad AffiGel® 15 permanufacturer's instructions.

Human Phosphodiesterase Preparations

[0924] Phosphodiesterase Activity Determinations

[0925] Phosphodiesterase activity of the preparations was determined asfollows. PDE assays utilizing a charcoal separation technique wereperformed essentially as described in Loughney et al. (1996). In thisassay, PDE activity converts [32P]cAMP or [32P]cGMP to the corresponding[32P]5′-AMP or [32P]5′-GMP in proportion to the amount of PDE activitypresent. The [32P]5′-AMP or [32P]5′-GMP then was quantitativelyconverted to free [32P]phosphate and unlabeled adenosine or guanosine bythe action of snake venom 5′-nucleotidase. Hence, the amount of[32P]phosphate liberated is proportional to enzyme activity. The assaywas performed at 30° C. in a 100 μL reaction mixture containing (finalconcentrations) 40 mM Tris HCl (pH 8.0), 1 μM ZnSO₄, 5 mM MgC₂, and 0.1mg/mL bovine serum albumin (BSA). Alternatively, in assays assessingPDE1-specific activity, incubation mixtures further incorporated the useof 0.1 mM CaCl₂ and 10 μg/mL calmodulin. PDE enzyme was present inquantities that yield <30% total hydrolysis of substrate (linear assayconditions). The assay was initiated by addition of substrate (1 mM[32P]cAMP or cGMP), and the mixture was incubated for 12 minutes.Seventy-five (75) μg of Crotalus atrox venom then was added, and theincubation was continued for 3 minutes (15 minutes total). The reactionwas stopped by addition of 200 μL of activated charcoal (25 mg/mLsuspension in 0.1 M NaH₂PO₄, pH 4). After centrifugation (750×g for 3minutes) to sediment the charcoal, a sample of the supernatant was takenfor radioactivity determination in a scintillation counter and the PDEactivity was calculated.

[0926] Inhibitor analyses were performed similarly to the methoddescribed in Loughney et al., J. Biol. Chem., 271, pp. 796-806 (1996),except both cGMP and cAMP were used, and substrate concentrations werekept below 32 nM, which is far below the Km of the tested PDEs.

[0927] Purification of PDE1A3 from SF9 Cells

[0928] Cell pellets (5 g) were mixed with 10 mL of Lysis Buffer (50 mMMOPS pH 7.5, 2 mM dithiothreitol (DTT), 2 mM benzamidine HCl, 5 μMZnSO₄, 0.1 mM CaCl₂, 20 μg/mL calpain inhibitors I and II, and 5 μg/mLeach of leupeptin, pepstatin, and aprotinin) at room temperature. Thecells were lysed by passage through a French® pressure cell(SLM-Aminco®, Spectronic Instruments, Inc., Rochester N.Y.). Theresultant lysate was centrifuged in a Beckman ultracentrifuge using atype T180 rotor at 45,000 rpm for 1 hr. The supernatant was recoveredand filtered through a 0.2 μm filter. This filtrate was applied to a2.6×90 cm column of SEPHACRYL® S-300 equilibrated in Column Buffer-A(Lysis Buffer containing 100 mM NaCl, and 2 mM MgCl₂). The column flowrate was adjusted to 1 mL/min and fractions of 7 mL were collected.Active fractions were pooled and supplemented with 0.16 mg ofcalmodulin. The enzyme was applied overnight at a flow rate of 0.2mL/min to an ACC-1 agarose immunoaffinity column as described in Hansenet al., Methods in Enzymology 159, pp. 453-557 (1988). The column waswashed with 5 volumes of Column Buffer B (Column Buffer A without NaCl)and followed by 5 volumes of Column Buffer C (Column Buffer A containing250 mM NaCl). The column was eluted with Column Buffer D (50 mM MOPS pH7.5, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 1 mM benzamidine HCl, 100 mM NaCl,20 μg/mL calpain inhibitors I and II, and 5 μg/mL each of leupeptin,pepstatin, and aprotinin) by applying one column volume at 0.1 mL/min,stopping flow for 1 hour, and then continuing elution at the same flowrate. Fractions of 0.5 mL were collected. Fractions displaying activitywere pooled, and first dialyzed against dialysis buffer containing 25 mMMOPS pH 7.5, 100 mM NaCl, 10 μM ZnSO₄, 1 mM CaCl₂, 1 mM DTT, and 1 mMbenzamidine HCl. A subsequent dialysis against dialysis buffercontaining 50% glycerol was performed prior to quick-freezing the samplewith dry ice and storage at −70° C. The resultant preparations wereabout 10 to 15% pure by SDS-PAGE. These preparations had specificactivities of about 5 to 20 μmol cAMP hydrolyzed per minute permilligram protein.

[0929] Purification of PDE1B from S. cerevisiae

[0930] Yeast cells (50 g) were thawed by mixing with 100 mL glass beads(0.5 mM, acid washed) and 200 mL Buffer A at room temperature. Buffer Aconsisted of 50 mM MOPS pH 7.5, 1 mM DTT, 2 mM benzamidine HCl, 0.01 mMZnSO₄, 5 mM MgCl₂, 20 μg/mL calpain inhibitors I and II, and 5 μg/mLeach of leupeptin, pepstatin, and aprotinin. The mixture was cooled to4° C., transferred to a Bead-Beater®, and the cells lysed by rapidmixing for 6 cycles of 30 seconds each. The homogenate was centrifugedfor 15 minutes in a Beckman J2-21M centrifuge using a JA-10 rotor at9,000 rpm and 4° C. The supernatant was recovered and centrifuged in aBeckman XL-80 ultracentrifuge using a TI45 rotor at 36,000 rpm for 45minutes at 4° C. The supernatant was recovered and PDE1B wasprecipitated by the addition of solid ammonium sulfate (0.33 g/mLsupernatant) while stirring in an ice bath and maintaining the pHbetween 7.0 and 7.5. This mixture then was centrifuged for 22 minutes ina Beckman J2 centrifuge using a JA-10 rotor at 9,000 rpm (12,000×g). Thesupernatant was discarded and the pellet was dissolved in 100 mL ofbuffer B (50 mM MOPS pH 7.5, 1 mM DTT, 1 mM benzamidine HCl, 0.01 mMZnSO₄, 2 mM MgCl₂, 2 mM CaCl₂, and 5 μg/mL each of leupeptin, pepstatin,and aprotinin). The pH and conductivity were corrected to 7.5 and 15-20milli-Siemens (mS), respectively. This solution was loaded onto a 20 mLcolumn of calmodulin-Agarose. that had been equilibrated with 10 columnvolumes of Buffer B at a rate of 1 mL/min. The flow-through wasreapplied to the column at least 5 times. The column was washed with 5volumes of Buffer B, 5 volumes of buffer B containing 250 mM NaCl, and 2volumes of Buffer B without NaCl again. Elution was accomplished byapplying one volume of Buffer C (50 mM MOPS pH 7.5, 1 mM EDTA, 1 mMEGTA, 1 mM DTT, 1 mM benzamidine HCl) at 0.33 mL/min, then stopping flowfor 1 hour before continuing the elution. Fractions of about 4 mL werecollected and assayed for PDE activity. Active fractions were pooled andconcentrated to a volume of 5 mL, using an Amicon ultrafiltrationsystem. The concentrate was then applied to a 320 mL Sephacryl® S-300column (1.6×150 cm) that had been equilibrated with at least 2 volumesof Buffer D (25 mM MOPS pH 7.5, 1 mM DTT, 1 mM benzamidine HCl, 0.01 mMZnSO₄, 2 mM CaCl, and 100 mM NaCl). The column was developed at a flowrate of 1 mL/min (11 cm/hr), and 5 mL fractions were collected. Theactivity peak was pooled and dialyzed overnight against Buffer Dcontaining 50% glycerol. The purified enzyme was frozen on dry ice andstored at −70° C. The resultant preparations were about >90% pure bySDS-PAGE. These preparations had specific activities of about 10 to 30μmol cGMP hydrolyzed per minute per milligram protein.

[0931] Purification of PDE1C3 from Sf9 Cells

[0932] Cell pellets (5 g) were thawed on ice with 20 mL of Lysis Buffer(50 mM MOPS pH 7.4, 10 μM ZnSO₄, 0.1 mM CaC₂, 1 mM DTT, 2 mM benzamidineHCl, 5 μg/mL each of pepstatin, leupeptin, and aprotinin). Cells werelysed by passage through a French® pressure cell (SLM-Aminco®,Spectronic Instruments) while temperatures were maintained below 10° C.The resultant cell homogenate was centrifuged at 36,000 rpm at 4° C. for45 min in a Beckman ultracentrifuge using a Type TI45 rotor. Thesupernatant was discarded and the resultant pellet was resuspended with40 mL of Solubilization Buffer (Lysis Buffer containing 1 M NaCl, 0.1 MMgCl₂, 1 mM CaCl₂, 20 μg/mL calmodulin, and 1% Sulfobetaine SB12 (Z3-12)by sonicating using a VibraCell tuner with a microtip for 3×30 seconds.This was performed in a crushed ice/salt mix for cooling. Followingsonication, the mixture was slowly mixed for 30 minutes at 4° C. tofinish solubilizing membrane bound proteins. This mixture wascentrifuged in a Beckman ultracentrifuge using a type TI45 rotor at36,000 rpm for 45 minutes. The supernatant was diluted with Lysis Buffercontaining 10 μg/mL calpain inhibitors I and II. The precipitatedprotein was centrifuged for 20 minutes at 9,000 rpm in a Beckman JA-10rotor. The recovered supernatant then was subjected to Mimetic Blue® APAgarose Chromatography.

[0933] To run the Mimetic Blue® AP Agarose Column, the resin initiallywas shielded by the application of 10 bed volumes of 1%polyvinylpyrrolidone (i.e., MW of 40,000) to block nonspecific bindingsites. The loosely bound PVP-40 was removed by washing with 10 bedvolumes of 2 M NaCl, and 10 mM sodium citrate pH 3.4. Just prior toaddition of the solubilized PCE1C3 sample, the column was equilibratedwith 5 bed volumes of Column Buffer A (50 mM MOPS pH 7.4, 10 μM ZnSO₄, 5mM MgCl₂, 0.1 mM CaCl₂, 1 mM DTT, 2 mM benzamidine HCl).

[0934] The solubilized sample was applied to the column at a flow rateof 2 mL/min with recycling such that the total sample was applied 4 to 5times in 12 hours. After loading was completed, the column was washedwith 10 column volumes of Column Buffer A, followed by 5 column volumesof Column Buffer B (Column Buffer A containing 20 mM 5′-AMP), andfollowed by 5 column volumes of Column Buffer C (50 mM MOPS pH 7.4, 10μM ZnSO₄, 0.1 mM CaCl₂, 1 mM DTT, and 2 mM benzamidine HCl). The enzymewas eluted into three successive pools. The first pool consisted ofenzyme from a 5-bed volume wash with Column Buffer C containing 1 mMcAMP. The second pool consisted of enzyme from a 10-bed volume wash withColumn Buffer C containing 1 M NaCl. The final pool of enzyme consistedof a 5-bed volume wash with Column Buffer C containing 1 M NaCl and 20mM cAMP.

[0935] The active pools of enzyme were collected and the cyclicnucleotide removed via conventional gel filtration chromatography orchromatography on hydroxyapatite resins. Following removal of cyclicnucleotides, the enzyme pools were dialyzed against Dialysis Buffercontaining 25 mM MOPS pH 7.4, 10 μM ZnSO₄, 500 mM NaCl, 1 mM CaCl₂, 1 mMDTT, 1 mM benzamidine HCl, followed by dialysis against Dialysis buffercontaining 50% glycerol. The enzyme was quick-frozen with the aid of dryice and stored at −70° C.

[0936] The resultant preparations were about >90% pure by SDS-PAGE.These preparations had specific activities of about 0.1 to 1.0 μmol cAMPhydrolyzed per minute per milligram protein.

[0937] Purification of PDE2 from S. cerevisiae

[0938] Frozen yeast cell pellets from strain YI34 (10 g, stored at −70°C.) were allowed to thaw on ice in 25 mL of Lysis Buffer (50 mM MOPS, pH7.2, 1 mM EDTA, 1 mM EGTA, 0.1 mM DTT, 0.1 mM4-(2-amino-ethyl)benzenesulfonyl fluoride (AEBSF), 1 μg/mL of pepstatin,leupeptin, aprotinin, calpain inhibitors I and II, and 2 mMbenzamidine). Cells were lysed by three passages through a French®pressure cell (SLM-Aminco®, Spectronic Instruments). The lysate wascentrifuged at 36,000 rpm in a Beckman Ultracentrifuge rotor Type 45Tifor 60 minutes at 4° C. The. supernatant was separated from sediment andpassed through a 15 mL Epoxy-cGMP Sepharose resin at 4° C. two times atabout 0.5 mL/min. The column subsequently was washed with 45 mL of WashBuffer 1 (50 mM MOPS, pH 7.2, 0.1 mM EDTA, 0.1 mM DTT). Following thiswash, the column was washed with 45 mL of Wash Buffer 2 (Wash Buffer 1containing 0.5 M NaCl). Following this salt wash, the column was washedwith 15 mL of Wash Buffer 3 (Wash Buffer 1 containing 0.25 M NaCl). Thecolumn was transferred to room temperature and allowed to warm.Approximately 25 mL of Elution Buffer (Wash Buffer 3 containing 10 mMcGMP, maintained at room temperature) was applied to the column and theeffluent was collected in 2 mL fractions. Small aliquots of each of thefractions were diluted 20-fold in PBS containing 5 mM MgCl₂ to allowhydrolysis of the competing ligand and to aid detection of PDE2activity. Active fractions were passed through a Pharmacia PD-10® gelfiltration column to exchange into Wash Buffer 3. This exchanged poolwas diluted 50% v/v with sterile 80% glycerol and stored at −20° C. Theresultant preparations were greater than 85% pure as judged by SDS-PAGEwith subsequent staining of protein by Coomassie R-250. Thesepreparations had specific activities of about 150 to 250 μmol cGMPhydrolyzed per minute per milligram protein.

[0939] Preparation of PDE3A from Sf9 Cells

[0940] Cells (2×1010) were suspended in Lysis Buffer containing 50 mMMOPS pH 7.5, 2 mM DTT, 2 mM benzamidine HCl, 5 μM ZnSO₄, 0.1 mM CaCl₂,20 μg/mL calpain inhibitors I and II, and 5 μg/mL each of leupeptin,pepstatin, and aprotinin. The mixture was sonicated twice for 30 secondsand the cells were lysed in a French® pressure cell (SLM-Aminco®,Spectronic Instruments) at 4° C. The lysate was centrifuged 100,000×gfor 45 minutes. The pellet was washed once in Lysis Buffer and suspendedin 46 mL Lysis Buffer with a Dounce homogenizer. Aliquots were stored at−70° C. These preparations had specific activities of about 1 to 2 nmolcAMP hydrolyzed per minute per milligram protein.

Human PDE4A, 4B, 4C, 4D Preparations

[0941] Preparation of PDE4A from S. cerevisiae

[0942] Yeast cells (50 g of yeast strain YI26 harboring HDUN1.46) werethawed at room temperature by mixing with 50 mL of Lysis Buffer (50 mMMOPS pH 7.5, 10 μM ZnSO₄, 2 mM MgCl₂, 14.2 mM 2-mercapto-ethanol, 5μg/mL each of pepstatin, leupeptin, aprotinin, 20 μg/mL each of calpaininhibitors I and II, and 2 mM benzamidine HCl). Cells were lysed in aFrench® pressure cell (SLM-Aminco®, Spectronic Instruments) at 10° C.The extract was centrifuged in a Beckman JA-10 rotor at 9,000 rpm for 22minutes at 4° C. The supernatant was removed and centrifuged in aBeckman TI45 rotor at 36,000 rpm for 45 minutes at 4° C.

[0943] PDE4A was precipitated from the high-speed supernatant by theaddition of solid ammonium sulfate (0.26 g/mL supernatant) whilestirring in an ice bath and maintaining the pH between 7.0 and 7.5. Theprecipitated proteins containing PDE4A were collected via centrifugationin a Beckman JA-10 rotor at 9,000 rpm for 22 minutes. The precipitatewas resuspended in 50 mL of Buffer G (50 mM MOPS pH 7.5, 10 μM ZnSO₄, 5mM MgCl₂, 100 mM NaCl, 14.2 mM 2-mercaptoethanol, 2 mM benzamidine HCl,5 ug/mL each of leupeptin, pepstatin, and aprotinin, and 20 μg/mL eachof calpain inhibitors I and II) and passed through a 0.45 μm filter.

[0944] The resuspended sample (50 to 100 mL) was loaded onto a 5×100 cmcolumn of Pharmacia SEPHACRYL® S-300 equilibrated in Buffer G. Enzymeactivity was eluted at a flow rate of 2 mL/min and pooled for laterfractionation.

[0945] The PDE4A isolated from gel filtration chromatography was appliedto a 1.6×20 cm column of Sigma Cibacron Blue Agarose-type 300 (10 mL)equilibrated in Buffer A (50 mM MOPS pH 7.5, 1.0 μM ZnSO₄, 5 mM MgCl₂,14.2 mM 2-mercaptoethanol, and 100 mM benzamidine HCl). The column waswashed in succession with 50 to 100 mL of Buffer A, 20 to 30 mL ofBuffer A containing 20 mM 5′-AMP, 50 to 100 mL of Buffer A containing1.5 M NaCl, and 10 to 20 mL of Buffer C (50 mM Tris HCl pH 8, 10 μMZnSO₄, 14.2 mM 2-mercaptoethanol, and 2 mM benzamidine HCl). The enzymewas eluted with 20 to 30 mL of Buffer C containing 20 mM cAMP.

[0946] The PDE activity peak was pooled, and precipitated with ammoniumsulfate (0.33 g/mL enzyme pool) to remove excess cyclic nucleotide. Theprecipitated proteins were resuspended in Buffer X (25 mM MOPS pH 7.5, 5μM ZnSO₄, 50 mM NaCl, 1 mM DTT, and 1 mM benzamidine HCl), and desaltedvia gel filtration on a Pharmacia PD-10® column per manufacturer'sinstructions. The enzyme was quick-frozen in a dry ice/ethanol bath andstored at −70° C.

[0947] The resultant preparations were about >80% pure by SDS-PAGE.These preparations had specific activities of about 10 to 40 μmol cAMPhydrolyzed per minute per milligram protein.

[0948] Preparation of PDE4B from S. cerevisiae

[0949] Yeast cells (150 g of yeast strain YI23 harboring HDUN2.32) werethawed by mixing with 100 mL glass beads (0.5 mM, acid washed) and 150mL Lysis Buffer (50 mM MOPS pH 7.2, 2 mM EDTA, 2 mM EGTA, 1 mM DTT, 2 mMbenzamidine HCl, 5 μg/mL each of pepstatin, leupeptin, aprotinin,calpain inhibitors I and II) at room temperature. The mixture was cooledto 4° C., transferred to a Bead-Beater®, and the cells lysed by rapidmixing for 6 cycles of 30 seconds each. The homogenate was centrifugedfor 22 minutes in a Beckman J2-21M centrifuge using a JA-10 rotor at9,000 rpm and 4° C. The supernatant was recovered and centrifuged in aBeckman XL-80 ultra-centrifuge using a TI45 rotor at 36,000 rpm for 45minutes at 4° C. The supernatant was recovered and PDE4B wasprecipitated by the addition of solid ammonium sulfate (0.26 g/mLsupernatant) while stirring in an ice bath and maintaining the pHbetween 7.0 and 7.5. This mixture was then centrifuged for 22 minutes ina Beckman J2 centrifuge using a JA-10 rotor at 9,000 rpm (12,000×g). Thesupernatant was discarded and the pellet was dissolved in 200 mL ofBuffer A (50 mM MOPS pH 7.5, 5 mM MgCl₂, 1 mM DTT, 1 mM benzamidine HCl,and 5 μg/mL each of leupeptin, pepstatin, and aprotinin). The pH andconductivity were corrected to 7.5 and 15-20 mS, respectively.

[0950] The resuspended sample was loaded onto a 1.6×200 cm column (25mL) of Sigma Cibacron Blue Agarose-type 300 equilibrated in Buffer A.The sample was cycled through the column 4 to 6 times over the course of12 hours. The column was washed in succession with 125 to 250 mL ofBuffer A, 125 to 250 mL of Buffer A containing 1.5 M NaCl, and 25 to 50mL of Buffer A. The enzyme was eluted with 50 to 75 mL of Buffer E (50mM Tris HCl pH 8, 2 mM EDTA, 2 mM EGTA, 1 mM DTT, 2 mM benzamidine HCl,and 20 mM cAMP) and 50 to 75 mL of Buffer E containing 1 M NaCl. The PDEactivity peak was pooled, and precipitated with ammonium sulfate (0.4g/mL enzyme pool) to remove excess cyclic nucleotide. The precipitatedproteins were resuspended in Buffer X (25 mM MOPS pH 7.5, 5 μM ZnSO₄, 50mM NaCl, 1 mM DTT, and 1 mM benzamidine HCl) and desalted via gelfiltration on a Pharmacia PD-10® column per manufacturer's instructions.The enzyme pool was dialyzed overnight against Buffer X containing 50%glycerol. This enzyme was quick-frozen in a dry ice/ethanol bath andstored at −70° C.

[0951] The resultant preparations were about >90% pure by SDS-PAGE.These preparations had specific activities of about 10 to 50 μmol cAMPhydrolyzed per minute per milligram protein.

[0952] Preparation of PDE4C from S. cerevisiae

[0953] Yeast cells (150 g of yeast strain YI30 harboring HDUN3.48) werethawed by mixing with 100 mL glass beads (0.5 mM, acid washed) and 150mL Lysis Buffer (50 mM MOPS pH 7.2, 2 mM EDTA, 2 mM. EGTA, 1 mM DTT, 2mM benzamidine HCl, 5 μg/mL each of pepstatin, leupeptin, aprotinin,calpain inhibitors I and II) at room temperature. The mixture was cooledto 4° C., transferred to a BEAD-BEATER®, and the cells lysed by rapidmixing for 6 cycles of 30 sec each. The homogenate was centrifuged for22 minutes in a Beckman J2-21M centrifuge using a JA-10 rotor at 9,000rpm and 4° C. The supernatant was recovered and centrifuged in a BeckmanXL-80 ultra-centrifuge using a TI45 rotor at 36,000 rpm for 45 minutesat 4° C.

[0954] The supernatant was recovered and PDE4C was precipitated by theaddition of solid ammonium sulfate (0.26 g/mL supernatant) whilestirring in an ice bath and maintaining the pH between 7.0. and 7.5.Thirty minutes later, this mixture was centrifuged for 22 minutes in aBeckman J2 centrifuge using a JA-10 rotor at 9,000 rpm (12,000×g). Thesupernatant was discarded and the pellet was dissolved in 200 mL ofBuffer A (50 mM MOPS pH 7.5, 5 mM MgCl₂, 1 mM DTT, 2 mM benzamidine HCl,and 5 μg/mL each of leupeptin, pepstatin, and aprotinin). The pH andconductivity were corrected to 7.5 and 15-20 mS, respectively.

[0955] The resuspended sample was loaded onto a 1.6×20 cm column. (25mL) of Sigma Cibacron Blue Agarose-type 300 equilibrated in Buffer A.The sample was cycled through the column 4 to 6 times over the course of12 hours. The column was washed in succession with 125 to 250 mL ofBuffer A, 125 to 250 mL of Buffer A containing 1.5 M NaCl, and then 25to 50 mL of Buffer A. The enzyme was eluted with 50 to 75 mL of Buffer E(50 mM Tris HCl pH 8, 2 mM EDTA, 2 mM EGTA, 1 mM DTT, 2 mM benzamidineHCl, and 20 mM cAMP) and 50 to 75 mL of Buffer E containing 1 M NaCl.The PDE4C activity peak was pooled, and precipitated with ammoniumsulfate (0.4 g/mL enzyme pool) to remove excess cyclic nucleotide. Theprecipitated proteins were resuspended in Buffer X (25 mM MOPS pH 7.2, 5μM ZnSO₄, 50 mM NaCl, 1 mM DTT, and 1 mM benzamidine HC1) and desaltedvia gel filtration on a Pharmacia PD-10® column per manufacturer'sinstructions. The enzyme pool was dialyzed overnight against Buffer Xcontaining 50% glycerol. This enzyme was quick-frozen in a dryice/ethanol bath and stored at −70° C.

[0956] The resultant preparations were about >80% pure by SDS-PAGE.These preparations had specific activities of about 10 to 20 μmol cAMPhydrolyzed per minute per milligram protein.

[0957] Preparation of PDE4D from S. cerevisiae

[0958] Yeast cells (100 g of yeast strain YI29 harboring HDUN4.11) werethawed by mixing with 150 mL glass beads (0.5 mM, acid washed) and 150mL Lysis Buffer (50 mM MOPS pH 7.2, 10 μM ZnSO₄, 2 mM MgCl₂, 14.2 mM2-mercaptoethanol, 2 mM benzamidine HCl, 5 μg/mL each of pepstatin,leupeptin, aprotinin, calpain inhibitors I and II) at room temperature.The mixture was cooled to 4° C., transferred to a Bead-Beater®, and thecells lysed by rapid mixing for 6 cycles of 30 sec each. The homogenatewas centrifuged for 22 minutes in a Beckman J2-21M centrifuge using aJA-10 rotor at 9,000 rpm and 4° C. The supernatant was recovered andcentrifuged in a Beckman XL-80 ultracentrifuge using a TI45 rotor at36,000 rpm for 45 minutes at 4° C. The supernatant was recovered andPDE4D was precipitated by the addition of solid ammonium sulfate (0.33g/mL supernatant) while stirring in an ice bath and maintaining the pHbetween 7.0 and 7.5. Thirty minutes later, this mixture was centrifugedfor 22 minutes in a Beckman J2 centrifuge using a JA-10 rotor at 9,000rpm (12,000×g). The supernatant was discarded and the pellet wasdissolved in 100 mL of Buffer A (50 mM MOPS pH 7.5, 10 μM ZnSO₄, 5 mMMgCl₂, 14.2 mM 2-mercaptoethanol, 100 mM benzamidine HCl, and 5 μg/mLeach of leupeptin, pepstatin, aprotinin, calpain inhibitor I and II).The pH and conductivity were corrected to 7.5 and 15-20 mS,respectively.

[0959] At a flow rate of 0.67 mL/min, the resuspended sample was loadedonto a 1.6×20 cm column (10 mL) of Sigma Cibacron Blue Agarose-type 300equilibrated in Buffer A. The column was washed in succession with 50 to100 mL of Buffer A, 20 to 30 mL of Buffer A containing 20 mM 5′-AMP, 50to 100 mL of Buffer A containing 1.5 M NaCl, and then 10 to 20 mL ofBuffer C (50 mM Tris HCl pH 8, 10 μM ZnSO₄, 14.2 mM 2-mercaptoethanol, 2mM benzamidine HCl). The enzyme was eluted with 20 to 30 mL of Buffer Ccontaining 20 mM cAMP.

[0960] The PDE4D activity peak was pooled and precipitated with ammoniumsulfate (0.4 g/mL enzyme pool) to remove excess cyclic nucleotide. Theprecipitated proteins were resuspended in Buffer X (25 mM MOPS pH 7.2, 5μM ZnSO₄, 50 mM, NaCl, 1 mM DTT, and 1 mM benzamidine HCl) and desaltedvia gel filtration on a Pharmacia PD-10® column per manufacturer'sinstructions. The enzyme pool was dialyzed overnight against Buffer Xcontaining 50% glycerol. This enzyme preparation was quick-frozen in adry ice/ethanol bath and stored at −70° C.

[0961] The resultant preparations were about >80% pure by SDS-PAGE.These preparations had specific activities of about 20 to 50 μmol cAMPhydrolyzed per minute per milligram protein.

[0962] Purification of PDE5 from S. cerevisiae

[0963] Cell pellets (29 g) were thawed on ice with an equal volume ofLysis Buffer (25 mM Tris HCl, pH 8, 5 mM MgCl₂, 0.25 mM DTT, 1 mMbenzamidine, and 10 μM ZnSO₄). Cells were lysed in a Microfluidizer®(Microfluidics Corp.) using nitrogen at 20,000 psi. The lysate wascentrifuged and filtered through 0.45 μm disposable filters. Thefiltrate was applied to a 150 mL column of Q SEPHAROSE® Fast-Flow(Pharmacia). The column was washed with 1.5 volumes of Buffer A (20 mMBis-Tris Propane, pH 6.8, 1 MM MgCl₂, 0.25 mM DTT, 10 μM ZnSO₄) andeluted with a step gradient of 125 mM NaCl in Buffer A followed by alinear gradient of 125-1000 mM NaCl in Buffer A. Active fractions fromthe linear gradient were applied to a 180 mL hydroxyapatite column inBuffer B (20 mM Bis-Tris Propane (pH 6.8), 1 mM MgCl₂, 0.25 mM DTT, 10μM ZnSO₄, and 250 mM KCl). After loading, the column was washed with 2volumes of Buffer B and eluted with a linear gradient of 0-125 mMpotassium phosphate in Buffer B. Active fractions were pooled,precipitated with 60%. ammonium sulfate, and resuspended in Buffer C (20mM Bis-Tris Propane, pH 6.8, 125 mM NaCl, 0.5 mM DTT, and 10 μM ZnSO₄).The pool was applied to a 140 mL column of SEPHACRYL® S-300 HR andeluted with Buffer C. Active fractions were diluted to 50% glycerol andstored at −20° C.

[0964] The resultant preparations were about 85% pure by SDS-PAGE. Thesepreparations had specific activities of about 3 μmol cGMP hydrolyzed perminute per milligram protein.

[0965] Preparation of PDE7 from S. cerevisiae

[0966] Cell pellets (126 9) were thawed and resuspended at roomtemperature. for about 30 minutes with an equal volume of Lysis Buffer(50 mM Tris HCl, pH 8, 1 mM EDTA, 1 mM DTT, 50 mM NaCl, 2 mM benzamidineHCl, and 5 μg/mL each of pepstatin, leupeptin, and aprotinin). The cellswere lysed at 0-4° C. with the aid of glass beads (125 mL) in aBead-Beater® for 6×30 second cycles. The lysate was centrifuged andfiltered through 0.45 μm disposable filters. The filtered extract (178mL) was distributed into 4 mL aliquots, quick-frozen with dry ice, andstored in a freezer at −70° C. These preparations were stable to severalcycles of freezing and thawing and had specific activities of about 50to 100 pmol cAMP hydrolyzed per minute per milligram protein.

Lipopolysaccharide-Stimulated TNFα Release from Human Peripheral BloodLymphocytes

[0967] To assess the ability of a compound to reduce TNFα secretion inhuman peripheral blood lymphocytes (PBL), the following tests wereperformed. Previous studies have demonstrated that incubation of humanPBL with cAMP-elevating agents, such as prostaglandin E21, forskolin,8-bromo-cAMP, or dibutryl-cAMP, inhibits the secretion of TNFα by thecells when stimulated by lipopolysaccharide (LPS; endotoxin).Accordingly, preliminary experiments have been performed to demonstratethat selective PDE4 inhibitors, such as rolipram, inhibit LPS-inducedTNFα secretion from human lymphocytes in a dose-dependent fashion.Hence, TNFα (secretion from human PBL was used as a standard for theability of a compound to elevate intracellular cAMP concentrationsand/or to inhibit PDE4 activity within the cell.

[0968] Heparinized blood (approximately 30 mL) drawn from humanvolunteers was mixed 1:1 with Dulbecco's modified phosphate-bufferedsaline. This mixture was mixed 1:1 with HISTOPAQUE® and centrifuged at1,500 rpm at room temperature without braking in the swinging bucket ofa Beckman model TJ6 centrifuge. Erythrocytes were centrifuged to thebottom of the tubes, and serum remained at the surface of the tubes. Alayer containing,lymphocytes sedimented between the serum andHISTOPAQUE® layers, and was removed by aspiration to a fresh tube. Thecells were quantified and adjusted to 3×10⁶ cells/mL and a 100 μLaliquot is placed into the wells of a 96 well plate. Test compounds andRPMI media (Gibco/BRL Life Sciences) are added to each of the wells 15minutes prior to addition of bacterial LPS (25 mg/mL). The mixture wasallowed to incubate for 20 hours at 37° C. in a humidified chamber. Thecells then were separated by centrifuging at 800 rpm for 5 minutes atroom temperature. An aliquot of 180 μL of supernatant was transferred toa new plate for determination of TNFα concentration. TNFα protein in thecell supernatant fluids was measured using a commercially availableenzyme-linked immunosorbent assay (ELISA) (CYTOSCREEN® Immunoassay Kitfrom Biosource International).

[0969] The cell-based assay provided the following results for variouspyrrolidine compounds of the present invention. The EC₅₀ values (i.e.,effective concentration of the compound capable of inhibiting 50% of thetotal TNFα) illustrate the ability of the present compounds to inhibitLPS-stimulated TNFα release from human PBL.

[0970] The table below illustrates the ability of compounds of formula(II) to inhibit PDE4 activity and TNFα release in vitro. In thefollowing table, the IC₅₀ values were determined against humanrecombinant PDE4. Sample PDE4 IC₅₀ PBL/TNFα EC₅₀ Number¹⁾Stereochemistry (M × 10⁻⁹) (M × 10⁻⁹) 1 Absolute, as drawn 87.0 1,205.82 Absolute, as drawn 260.0 1,900.0 3 Relative stereochemistry 180.03,261.7 as drawn; racemic 4 Relative, stereochemistry 190.0 3,611.5 asdrawn; racemic 5 Relative, stereochemistry 75.0 1,551.3 as drawn;racemic 6 Relative, stereochemistry 75.0 3,657.5 as drawn; racemic 7Absolute, as drawn 5,800.0 8 Absolute, as drawn 784.0 909.6 9 Absolute,as drawn 13,000.0 10 Absolute, as drawn 7,900.0 11 Absolute, as drawn3,700.0 12 Absolute, as drawn 2,600.0 13 Absolute, as drawn 1,000.02,339.5 14 Absolute, as drawn 900.0 2,981.5 15 Relative stereochemistry4.3 108.8 as drawn; racemic, mixture of ether isomers 16 Relativestereochemistry 7.3 46.4 as drawn; racemic, mixture of ether isomers 17Absolute, as drawn 2,211.6 3,447.3 18 Absolute, as drawn 1,027.3 5,101.619 Absolute, as drawn 1,974.0 1,951.1 20 Absolute, as drawn 536.0 170.021 Absolute, as drawn 16.2 278.0 22 Absolute, as drawn 520.4 164.0 23Absolute, as drawn 1,592.2 24 Absolute, as drawn; 1.6 40.0 mixture ofether isomers 25 Absolute, as drawn; 2.8 12.2 mixture of ether isomers26 Absolute, as drawn; 35.0 106.0 mixture of ether isomers 27 Absolute,as drawn; 1.8 36.0 mixture of ether isomers 28 Absolute, as drawn 23.0241.0 29 Absolute, as drawn 4.9 78.0 30 Absolute, as drawn 100.0 440.031 Absolute, as drawn 3.6 35.0 32 Absolute, as drawn 1,000.0 801.0 33Absolute, as drawn 2,100.0 34 Absolute, as drawn 402.6 250.0 35Absolute, as drawn 35.6 20.3 36 Absolute, as drawn 187.2 1,600.0 37Absolute, as drawn .768 72.0 38 Absolute, as drawn 5.9 36.0 39 Absolute,as drawn 2.7 48.1 40 Absolute, as drawn 98.4 139.1 41 Absolute, as drawn27.0 266.9 42 Absolute, as drawn 7.5 171.7 43 Absolute, as drawn 12.5145.8 44 Absolute, as drawn 41.2 238.0 45 Absolute, as drawn 247.6 694.046 Absolute, as drawn 1,805.9 13,317.0 47 Absolute, as drawn 2,727.420,000.0 48 Absolute, as drawn 89.7 446.0 49 Absolute, as drawn 14.326.2 50 Absolute, as drawn 44.8 151.2 51 Absolute, as drawn 44.7 72.6 52Absolute, as drawn 26.7 53 Absolute, as drawn; 116.3 112.6 mixture oftetrahydrofuryl isomers 54 Absolute, as drawn; 464.7 mixture of 2,2-dimethyl-4-oxo-4- pyrrolidin-1-yl- butyric acid and 3,3-dimethyl-4-oxo-4- pyrrolidin-1-yl- butyric acid amides 55 Absolute, asdrawn 1,842.1 56 Absolute, as drawn 4.0 57 Absolute, as drawn 95.6 58Absolute, as drawn 59 Racemic; relative 58.0 170.0 stereochemistry asshown 60 Racemic; relative 74.0 44.0 stereochemistry as shown 61Racemic; relative 18.3 57.8 stereochemistry as shown 62 Racemic,relative 6.8 10.2 stereochemistry as shown 63 Racemic, relative 51.4267.4 stereochemistry as shown, nonbornyl residue racemic 64 Racemic,relative 8.5 36.2 stereochemistry as shown, nonbornyl residue racemic 65Racemic, relative 220.0 181.0 stereochemistry as shown 66 Absolute 14.071.6 stereochemistry as shown 67 Absolute stereochemistry 514.7 603.3 asshown 68 Absolute stereochemistry 61.1 169.9 as shown 69 Absolutestereochemistry 13.3 57.0 as shown 70 Absolute stereochemistry 498.5547.2 as shown; single undefined alcohol isomer 1 71 Absolutestereochemistry 1,707.2 as shown; single undefined alcohol isomer 2 72Absolute, as drawn 2,452.6 73 Absolute, as drawn 9,131.0 74 Absolute, asdrawn 352.3 557.3 75 Absolute, as drawn 45.1 121.0 76 Absolute, as drawn36.6 173.0 77 Absolute, as drawn 188.7 580.0 78 Absolute, as drawn 760.11,288.6 79 Absolute, as drawn 1,639.0 2,366.6 80 Absolute, as drawn300.0 272.4 81 Absolute, as drawn 700.0 624.8 82 Absolute, as drawn389.8 490.0 83 Absolute, as drawn 172.0 51.0 84 Absolute, as drawn 21.740.0 85 Absolute, as drawn 3,576.8 86 Absolute, as drawn 6,077.6 87Absolute, as drawn 896.6 934.4 88 Absolute, as drawn 953.4 629.5 89Absolute, as drawn 699.0 860.0 90 Absolute, as drawn 69.4 61.0 91Absolute, as drawn 150.0 44.0 92 Absolute, as drawn 439.4 93 Absolute,as drawn 33.1 7.8 94 Absolute 238.2 1,800.0 stereochemistry as shown

[0971] The data presented above shows that the present compounds arepotent inhibitors of PDE4, e.g., the compounds have an IC₅₀ vs. humanrecombinant PDE4 of about 700 μM to about 15 μM. Preferred compoundshave an IC₅₀ of about 100 nM or less, and especially preferred compoundshave an IC₅₀ of about 50 nM or less.

[0972] Similarly, preferred compounds have a PBL/TNFα EC₅₀ about 500 nMor less, and preferably about 200 nM or less. More preferred compoundshave a PBL/TNFα EC₅₀ of about 100 nM or less.

[0973] To achieve the full advantages of the present invention, thecompounds have an IC₅₀ vs. human recombinant PDE4 of about 100 nM orless and a PBL/TNFα EC₅₀ of about 500 nM or less. More preferably, thecompounds have an IC₅₀ of about 50 nM or less and a PBL/TNFα EC₅₀ ofabout 100 nM or less.

ANIMAL MODELS Assay for Inhibition of Serum TNFα Levels in Mammals(Mouse/TNFα ED₅₀ (mg/kg))

[0974] In order to assess the ability of a compound to reduce serum TNFαlevels in mammals, the following protocol was employed. Those skilled inthe art appreciate that previous studies have demonstrated thatincubation of LPS-activated human monocytes with agents that can elevatecAMP, like PGE2, forskolin, and the dbcAMP, inhibited secretion of TNFα.PDE4 inhibitors like rolipram, which also elevate cAMP, have been foundto inhibit serum TNFα as well. Rolipram has also been found to inhibitsecretion of TNFα from LPS-activated mouse macrophages. Accordingly, invivo efficacy of a PDE4 reducing compound was shown by dosing withcompound and measuring reduction of serum TNFα levels in LPS-injectedmice. Female C3H mice, 20-25 gm body. weight, were fasted overnight anddosed intraperitoneally with test compound in appropriate vehicle 60minutes before LPS injection. Five μg of LPS was then injectedintraperitoneally into the mice. Ninety minutes after LPS injection,mice were bled from the heart. Blood was allowed to clot overnight at40° C. Samples were centrifuged for 10 minutes in a microcentrifuge andthe serum removed and stored at −20° C. until analysis. Serum levels ofTNFα were subsequently measured using a commercially available ELISA kit(Genzyme) following the protocol enclosed in the kit. The percent ofinhibition of serum TNFα levels caused by the compound was determinedrelative to serum TNFα levels in control mice receiving vehicle alone.

Combined Mouse Endotoxin-Stimulated TNFα Release and Locomotor ActivityAssay (ED₅₀ (mg/kq))

[0975] The purpose of this study was to determine the efficacy of PDE4inhibitors in vivo in an LPS mouse model together with a determinationwith respect to central nervous system (CNS) side-effects manifested bya decrease in spontaneous mobility.

[0976] The test animals were female Balb/c mice, having an averageweight of about 20 g. The PDE4 inhibitors, formulated in 30% Cremophor®EL, were administered via intraperitoneal (i.p.) injections at doses of0.1, 1.0, 10.0, and 100 mg/kg. Individual dose volumes (about 150 μL)were adjusted based on the body weights measured. One hour later, 5mg/kg LPS in a final volume of 200 μL was injected via the tail vein toeach animal. Ninety minutes following the LPS treatment, the animalswere bled and serum samples were collected before being stored at −70°C. until assayed.

[0977] For efficacy determination, the serum samples were dilutedtwo-fold and TNFα levels were determined using the CYTOSCREEN®Immunoassay Kit (Biosource International). The data were averagedbetween triplicate sample subjects for each of the tested compounds.

[0978] Movement of the X-Y plane, or rearing up on the hind legs, wasquantified by counting the number of “light-beam” crosses per unit oftime. A decrease in the number of activity events is directlyproportional to the mobility or immobilization of the animal Thequantitative scoring correlated well with the subjective measurementsdescribed above.

[0979] The following table summarizes the Mouse/TNFα ED₅₀ (mg/kg)results obtained by the above-described method: Mouse/TNFα SampleNumber¹⁾ ED₅₀ (mg/kg) ED₅₀ (mg/kg)³⁾ 29 — 9.8 31 3 83 61 0.2 >50 620.08 >50 66 5 >50 67 — >50 68 12 20 69 7 <0.5

[0980] It also was determined that compounds of formula (II) have fewercentral nervous system side effects compared to rolipram and tocompounds disclosed in Feldman et al. U.S. Pat. No. 5,665,754. It alsowas found that central nervous system activity is related to theabsolute stereochemistry of the present compounds.

[0981] It is known that stereoisomers of drugs can have substantiallydifferent biological activities, e.g., potency, selectivity, absorption,distribution metabolism, execution, and side effect profiles. In thepresent invention, the enantiomers and diastereomers represented bycompounds (A)-(D) in the following table were tested for effects on invitro PDE activity, cell-based LPS/TNFα release from human peripheralblood lymphocytes (PBLs), mouse mobility, and ferret emesis.

[0982] As shown in the following table, compounds (C) and (A) (i.e.,Samples 66 and 69, respectively) show similar inhibition of PDE4 andLPS-stimulated TNFα release, but substantially different behavioralprofiles. Compounds (C) and (A), which exhibit less CNS activity, arederived from the predominant product of the [3+2] azomethine ylidecyclization to the chiral α,β-unsaturated amide. Thus, the absolutestereochemistry of a PDE4 inhibitor of the present invention contributessignificantly to the behavioral profile of the compound. PDE4 Mouse/TNFαCNS Side Examples Compound IC₅₀ (nM) ED₅₀ (mg/kg) Effects¹⁾ (A)

13.3 7 Severe (C)

14.0 5 No effect (B)

61.1 12 No effect (D)

514.7 — No effect Sample No. 62

6.8 0.08 Little to no effect (at 50 mg/kg) Sample No. 61

18.3 0.2 Little to no effect (at 50 mg/kg) # 8(C), 8(D), and 8(B).However, mice were affected at all doses when given Example 8(A).Furthermore, at the highest dose of Example 8(A), mice became moribundand died within 10 minutes of treatment.

[0983] The data presented above show that compounds of formula (II) arepotent and selective inhibitors of PDE4. As an important addedadvantage, the compounds of formula (II) also reduced or eliminated theadverse CNS side effects associated with prior PDE4 inhibitors.Compounds of formula (II) were further tested for emetogenic propertiesin animal models to further illustrate the efficacy of the compounds.The method and results of the emetogenic test are set forth below.

Emetic Modeling in the Ferret Following Oral and Intravenous Dosing withPDE4-Selective Inhibitors

[0984] This study was conducted to investigate the emetogenic propertiesof PDE4 inhibitors in vivo. The ferret previously has been establishedas a valuable tool for assessing emesis following exposure to testcompounds. Previous studies indicated that the emetic response of aferret to many PDE4 inhibitors is predictive of the disposition ofhumans toward the same test compounds. Therefore, lack of and/ordecrease in emetic potential of test compounds in ferrets predicts afavorable nonemetic effect in humans. Emesis is a complex physiologicalresponse to noxious agents that can be intiated. peripherally orcentrally. Hence, PDE4-selective agents were tested when administeredboth intravenously or orally.

[0985] The test animals were adult, castrated, and descented maleferrets (species=Mustela putorius furo, Strain=Sable) ranging in weightfrom about 1 to 1.5 kg. The tests were performed in quadruplicate onanimals that were naive to PDE4 inhibitors. The PDE4 inhibitors wereformulated in 10% Polyoxyl-35 castor oil (CREMOPHOR® EL, available fromBASF Corporation, Parsippany, N.J.) in phosphate buffered saline (PBS),and were administered via i.v. injections into an indwelling cathetersurgically positioned in the right. external jugular vein at a rate of0.66 mL per kg body weight. PDE4 inhibitors for oral consumption wereformulated in 30%. CREMOPHOR® EL in PBS, and administered by intubatinganimals with a 16-gauge feeding needle into the stomach. The animalsreceived the PDE4 inhibitors in a volume of 1.33 mL per kg body weight.

[0986] All animals were fasted for 8 to 12 hours prior to administrationof PDE4 inhibitors. Following administration of a PDE4 inhibitor, emeticand behavioral responses were quantified for three hours post dosing.The total number of emetic responses and vomiting episodes werequantified during the observation interval. In addition, latency time tofirst emetic episode, duration of emesis episodes, and gross behavioralchanges including ataxia, profuse and viscous salivation, mouth clawing,hyperventilation, backward walking, flattened body posture,hyperactivity, lip licking, and general appearance were recorded.

[0987] For comparative purposes, the emetogenic effect of Samples 66 and69 were tested intravenously at 1.0, 2.5, 5.0, and 10 mg/kg and orallyat 2.5, 10, 17, and 25 mg/kg. The results are summarized in thefollowing table: COMPARATIVE RESULTS Compound (A) (Sample 69) Number ofEmetic Events Oral (mg/kg) Vomits Retches Total Responders 2.5 0 0 0 0/410.0 5 27 32 3/4 17.0 7 51 58 3/4 25.0 26 88 114 4/4 Intravenous (mg/kg)Vomits Retches Total Responders 1.0 0 0 0 0/4 2.5 0 3 3 1/4 5.0¹⁾ 0 300300 2/2 10.0 — — — — Compound (C) (Sample 66) Number of Emetic EventsOral (mg/kg) Vomits Retches Total Responders 2.5 0 0 0 0/4 10.0 8 14 222/4 17.0 1 17 18 2/3 25.0 12 61 73 4/4 Intravenous (mg/kg) VomitsRetches Total Responders 1.0 0 0 0 0/4 2.5 0 0 0 0/4 5.0¹⁾ 0 10 10 2/410.0 4 27 31 4/4

[0988] In general, both compounds (C) and (A), delivered either orallyor via intravenous injection, produced a clear dose response in terms ofemetic behavior. Compound (A) produced a much stronger emetic responsethan compound (C). This was readily apparent when the responses to oraldosing was compared. For example, at a dose of 25 mg/kg body weight,compound (A) produced more retching and vomiting episodes than the sameoral dose of compound (C). In addition, the number of retches andvomiting events per episode was much greater for compound (A) thancompound (C) in this dose group. A similar trend was apparent at oraldosages of 17 and 11 mg/kg body weight, with compound (A) exhibiting astronger response than compound (C). There were no apparent differencesobserved between the lowest dosed groups for both molecules. In thesecases, some minor lip licking/mouth pawing was evident with bothcompounds, but no emetic responses were observed.

[0989] The results of oral dosing contrast markedly with that ofintravenous dosing. At an intravenous dose of 5 mg/kg body weight ofcompound (A), one of the tested animals died almost immediately afterdosing (within 5 minutes), whereas the second animal was clearlydistressed, but recovered after 3 hours. The distress can be attributedeither to an acute toxicity event or to an exaggerated pharmacologicalresponse to centrally mediated emesis. It also was noted that thedistressed and labored breathing in these dosed animals was difficult todistinguish from extreme retching behavior. The effects were not nearlyas severe with intravenous administration of compound (C) as shown inthe above table. Although all animals exhibited emetic behavior at the10 mg/kg body weight dose with compound (C), none displayed the distressassociated with the 5 mg/kg dose of compound (A). With the exception ofthe 5 mg/kg body weight dose of compound (A), all of the animalsrecovered from their treatment and appeared normal. Assay Example 101Example 264 Example 109 Example 268 Example 195 PDE4B IC₅₀ (μM) 0.0110.003 0.02 0.015 0.007 Cell based EC₅₀ 0.03 0.010 0.03 0.006 0.03 (μM)Mouse LPS 3 1 5 5 9 Challenge ED₅₀ (mg/kg) Mouse 100 <100 100 100 100Inhibition of Spontaneous Mobility ED₅₀ (mg/kg)

[0990] The results summarized in the above tables show that thecompounds of the present invention are useful for selectively inhibitingPDE4 activity in a mammal, without exhibiting the adverse CNS and emeticeffects associated with prior PDE4 inhibitors.

[0991] Obviously, many modifications and variations of the invention ashereinbefore set forth can be made without departing from the spirit andscope thereof and, therefore, only such limitations should be imposed asare indicated by the appended claims.

What is claimed is:
 1. A compound having a formula:

wherein R¹ is selected from the group consisting of hydrogen, loweralkyl, bridged alkyl, aryl, cycloalkyl, a 4-, 5-, or 6-memberedsaturated heterocycle, heteroaryl, C₁₋₄alkylenearyl, C₁₋₄alkyleneOaryl,C₁₋₄alkyleneheteroaryl, C₁₋₄alkyleneHet, C₂₋₄alkylenearylOaryl,C₁₋₄alkylene bridged alkyl, C₁₋₄alkylenecycloalkyl, substituted orunsubstituted propargyl, substituted or unsubstituted allyl, andhalocycloalkyl; R² is selected from the group consisting of hydrogen,methyl, and halo-substituted methyl, e.g., CHF₂; R³ is selected from thegroup consisting of C(═O)OR⁷, C(═O)R⁷, NHC(═O)OR⁷, C₁₋₃alkyleneC(═O)OR⁸,C₁₋₃alkyleneC(═O)R⁸, C(═NH)NR⁸R⁹, C(═O)NR⁸R⁹, C(═O)C(═O)NR⁸R⁹,C(═O)C(═O)OR⁸, C₁₋₄alkyleneOR⁸, aryl, C₁₋₃alkylenearyl,C₁₋₃alkyleneheteroaryl, So₂heteroaryl, Het, and heteroaryl; R⁴ isselected from the group consisting of hydrogen, lower alkyl, haloalkyl,cycloalkyl, and aryl; R⁵ is selected from the group consisting ofhydrogen, lower alkyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, andaryl; R⁶ is selected from the group consisting of hydrogen, lower alkyl,and C(═O)R⁷; R⁷ is selected from the group consisting of lower alkyl,branched or unbranched, C₁₋₄alkylenearyl, cycloalkyl, Het,C₁₋₄alkylenecycloalkyl, heteroaryl, and aryl, each optionallysubstituted with one or more of OC(═O)R⁸, C(═O)OR⁸, OR⁸, NR⁸R⁹, or SR⁸;R⁸ and R⁹, same or different, are selected from the group consisting ofhydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, C(═O)Oalkyl,C(═O)Oaryl, C(═O)alkyl, alkylSO₂, haloalkylSo₂, C(═O)C₁₋₃alkylenearyl,C(═O)OC₁₋₄alkylenearyl, C₁₋₄alkylenearyl, and Het, or R⁸ and R⁹ togetherform a 4-membered to 7-membered ring; R¹⁰ is selected from the groupconsisting of hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, C(═O)alkyl,C(═O)cycloalkyl, C(═O)aryl, C(═O)Oalkyl, C(═O)Ocycloalkyl, C(═O)aryl,CH₂OH, CH₂Oalkyl, CHO, CN, NO₂, and SO₂R¹¹; R¹¹ is selected from thegroup consisting of alkyl, cycloalkyl, trifluoromethyl, aryl, aralkyl,and NR⁸R⁹; and salts and solvates thereof.
 2. The compound of claim 1having the structure:


3. The compound of claim 1 wherein R¹ is selected from the groupconsisting of:


4. The composition of claim 1 wherein R³ is selected from the groupconsisting of:


5. The compound of claim 1 wherein R⁴ is selected from the groupconsisting of hydrogen, methyl, trifluoromethyl, cyclopropyl, benzyl,and phenyl.
 6. The compound of claim 1 wherein R⁵ is lower alkyl.
 7. Thecompound of claim 1 wherein R⁶ is selected from the group consisting ofhydrogen, acetyl, and benzoyl.
 8. The compound of claim 1 wherein R⁷ islower alkyl.
 9. The compound of claim 1 wherein R⁸ and R⁹,independently, are hydrogen, lower alkyl, C(═O)C₁₋₃alkylenearyl, aryl,heteroaryl, Het, or cycloalkyl, or together form a 5-membered or6-membered ring.
 10. The compound of claim 1 wherein R¹ is selected fromthe group consisting of cyclopentyl, tetrahydrofuryl, indanyl,norbornyl, phenethyl, phenylbutyl, methylenecyclopropyl,methylenetetrahydrofuryl, ethylenethienyl, C₁₋₄alkylenecyclopentyl,methyleneindanyl, C₁₋₄alkylenephenyl, phenylpropargyl, phenylallyl,3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)methyl, C₁₋₄alkylenephenoxy,C₁₋₄alkylenebiphenyl, C₁₋₄alkylenecyclohexyl, pyranyl, methylene bridgedalkyl, tetrahydronaphtyl, decahydronaphthyl, and C₁₋₆alkyl, optionallysubstituted with one or more phenyl, hydroxy, methoxy, methyl, ethyl,trifluoromethyl, fluoro, phenoxy, t-butyl, methoxy, cyclopropyl, andhalophenyl; R² is selected from the group consisting of methyl anddifluoromethyl; R³ is selected from the group consisting of CO₂CH₃,C(═O)CH₂OH, C(═O)CH(CH₃)OH, C(═O)C(CH₃)₂OH, C(═O)C(═O)NH₂, C(═O)C(═O)OH,C(═O)CH₂NH₂, C(═O)CH(OH)CH₂OH, C(═O)CH(OH)CH₂CH₂CH₃,

R⁴ is hydrogen; R⁵ is methyl; R⁶ is hydrogen; R⁷ is methyl; R⁸ and R⁹,independently, are selected from the group consisting of hydrogen andlower alkyl, or form a 5-membered or 6-membered ring, and R¹⁰ ishydrogen.
 11. The compound of claim 1 selected from the group consistingof:4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-(1-hydroxy-1-methylethyl)-3-methylpyrrolidine-1-carboxylicacid methyl ester1-[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(1-hydroxy-1-methylethyl)-3-(S)-methylpyrrolidin-1-yl]-2-hydroxyethanonetrans-(±)-3-(1-Hydroxyethyl)-4-[3-(indan-2-yloxy)-4-methoxyphenyl]-3-methylpyrrolidine-1-carboxylicacid methyl ester trans4-[3-Exo-(Bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]-3-(1-hydroxyethyl)-3-methylpyrrolidine-1-carboxylicacid methyl estertrans-3-(1-Hydroxyethyl)-4-[4-methoxy-3-(1-methyl-3-phenylpropoxy)phenyl]-3-methylpyrrolidine-1-carboxylicacid methyl ester1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(phenylmethoxy)ethan-1-one1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyethan-1-oneN-{3-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-3-oxopropyl}(phenylmethoxy)carboxamide1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-3-amino-propan-1-onePhenylmethyl4-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-4-oxobutanoate4-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-4-oxobutanoicacidN-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoethyl}(phenylmethoxy)carboxamide1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-amino-ethan-1-one3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl-4-methylpiperazinylketone p13-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinylmorpholin-4-yl ketone1-[3-((1S)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-[(2S,1R,5R)-5-methyl-2-(methylethyl)cyclohexyloxy]-ethan-1-one3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl2-methyl-(1,3-thiazol-4-yl) ketone3-{[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]sulfonyl}-pyridine1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(phenylmethoxy)ethan-1-one1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyethan-1-oneMethyl2-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoacetateN-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1,1-dimethyl-2-oxoethyl}(phenylmethoxy)carboxamide1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-amino-2-methylpropan-1-oneMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylate4-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2,2-dimethyl-4-oxobutanoicacid3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl2-methyl(1,3-thiazol-4-yl) ketone3-((1R)-1-Hydroxyethyl)(4S,3R)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylcyclopentyloxolan-3-yl ketoneN-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoethyl}(phenylmethoxy)carboxamide1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-aminoethan-1-one(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-(2-pyridyl)pyrrolidin-3-yl]ethan-1-ol(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-(3-pyridyl)pyrrolidin-3-yl]ethan-1-ol(1R)-1-[(3S,4s)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-pyrimidin-2-ylpyrrolidin-3-yl]ethan-1-ol(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-(2-pyridyl)pyrrolidin-3-yl]ethan-1-ol(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-(3-pyridyl)pyrrolidin-3-yl]ethan-1-olMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenoxyphenoxy)phenyl]-3-methylpyrrolidinecarboxylateMethyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenoxyphenoxy)phenyl]-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenylphenoxy)phenyl]-3-methylpyrrolidinecarboxylateMethyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenylphenoxy)phenyl]-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(4-methoxy-3-phenoxyphenyl)-3-methylpyrrolidinecarboxylateMethyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-(4-methoxy-3-phenoxyphenyl)-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[3-(4-fluorophenoxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylate Methyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(4-methoxy-3-(1,3-thiazol-2-yloxy)phenyl)-3-methylpyrrolidinecarboxylateMethyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-(4-methoxy-3-(1,3-thiazol-2-yloxy)phenyl)-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-benzimidazol-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylateMethyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-(3-benzimidazol-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylpropoxy)phenyl]-3-methylpyrrolidinecarboxylateMethyl 3-((1S)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylpropoxy)phenyl]-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenylbutoxy)phenyl]-3-methylpyrrolidinecarboxylateMethyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(4-phenylbutoxy)phenyl]-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(2-phenylethoxy)phenyl]-3-methylpyrrolidinecarboxylateMethyl3-((1S)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(2-phenylethoxy)phenyl]-3-methylpyrrolidinecarboxylate(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-(2-pyridylmethyl)pyrrolidin-3-yl]ethan-1-ol(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-(3-pyridylmethyl)pyrrolidin-3-yl]ethan-1-ol(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-(4-pyridylmethyl)pyrrolidin-3-yl]ethan-1-olPhenylmethyl 3-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]propanoate3-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]propanoicacid Phenylmethyl2-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]acetate2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]aceticacid2-[(3R)-3-((1R)-1-Hydroxyethyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-1-phenylethylacetate1-[(3R)-3-((1R)-1-Hydroxyethyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxy-2-phenylethan-1-one1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(phenylmethoxy)ethan-1-one1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyethan-1-one2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-1-methyl-2-oxoethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-hydroxypropan-1-one{[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]carbonyl}-cyclopropylacetate3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinylhydroxycyclopropyl ketone2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1,1-dimethyl-2-oxoethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxy-2-methylpropan-1-oneMethyl2-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoacetate2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-aceticacid2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-acetamide2-{(3S,4S)-3-((R)-1-Hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)-phenyl]-3-methylpyrrolidin-1-yl}-2-oxo-acetamide2-((3S,4S)-3-((R)-1-Hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoromethyl-phenyl)prop-2-ynyloxy]-phenyl}-3-methylpyrrolidin-1-yl)-2-oxo-acetamide2-[(3S,4S)-4-{3-[3-(4-Fluorophenoxy)propoxy]-4-methoxyphenyl}-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-oxo-acetamide2-[(3S,4S)-4-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-oxo-acetamide2-{(3S,4S)-3-((R)-1-Hydroxyethyl)-4-[3-(indan-2-yloxy)-4-methoxyphenyl]-3-methylpyrrolidin-1-yl}-2-oxo-acetamide2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-N-methyl-2-oxoacetamide1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-piperidylethane-1,2-dione2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-N-cyclopentyl-2-oxoacetamide2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-N-benzylacetamideN-{(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-butyl-2-oxoethyl}(phenylmethoxy)carboxamide(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-aminohexan-1-oneN-{(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-(methylethyl)-2-oxoethyl}(phenylmethoxy)carboxamide(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-amino-3-methylbutan-1-one2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-1-cyclohexyl-2-oxoethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-cyclohexyl-2-hydroxyethan-1-one1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2R)-2-cyclohexyl-2-acetoxyethan-1-one(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-cyclohexyl-2-hydroxyethan-1-oneN-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-(1S)-1-butyl-2-oxoethyl}(phenylmethoxy)carboxamide1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-aminohexan-1-one(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-butyl-2-oxoethylacetate(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyhexan-1-oneN-{2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-(1S)-2-oxo-1-benzylethyl}(phenylmethoxy)carboxamide1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-amino-3-phenylpropan-1-oneN-{(1R)-2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxo-1-benzylethyl}(phenylmethoxy)carboxamide(2R)-1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-amino-3-phenylpropan-1-one2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxo-1-propylethylacetate 1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxypentan-1-one1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-(phenylmethoxy)propan-1-one1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-(hydroxy)propan-1-oneN-((1R)-2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-(tert-butyl)-2-oxoethyl)(tert-butoxy)carboxamide(2R)-1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-3,3-dimethylbutan-1-oneN-{2-[(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1R)-2-oxo-1-[(phenylmethoxy)methyl]ethyl}(tert-butoxy)carboxamideN-(2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-2-oxo-1-[(phenylmethoxy)methyl]ethyl)(tert-butoxy)carboxamideN-(2-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1R)-1-(hydroxymethyl)-2-oxoethyl)(tert-butoxy)carboxamide1-{(3S,4S)-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2R)-2-amino-3-hydroxypropan-1-onehydrochloride2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-cyclohexyl-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-cyclohexyl-2-hydroxyethan-1-one(1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-cyclohexyl-2-oxoethylacetate(2R)-1-{3-((1)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-cyclohexyl-2-hydroxyethan-1-oneN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-butyl-2-oxoethyl)(phenylmethoxy)carboxamide(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-aminohexan-1-oneN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-(methylethyl)-2-oxoethyl)(phenylmethoxy)carboxamide(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-3-methylbutan-1-one1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-acetylthioethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-acetylthioethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-sulfanylethan-1-oneN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoethyl)(phenylmethoxy)carboxamide1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-aminoethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]l-3-methylpyrrolidinyl}-2-[(methylsulfonyl)amino]ethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-{[(trifluoromethyl)sulfonyl]amino}ethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(dimethylamino)ethan-1-oneN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-methyl-2-oxoethyl)(phenylmethoxy)carboxamide1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-aminopropan-1-oneN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-methyl-2-oxoethyl)(phenylmethoxy)carboxamide(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-aminopropan-1-oneN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-(methylethyl)-2-oxoethyl)(phenylmethoxy)carboxamide1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-amino-3-methylbutan-1-oneN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-(2-methylpropyl)-2-oxoethyl)(phenylmethoxy)carboxamide1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-amino-4-methylpentan-1-oneN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1-(2-methylpropyl)-2-oxoethyl)(phenylmethoxy)carboxamide(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-4-methylpentan-1-oneN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-butyl-2-oxoethyl)(phenylmethoxy)carboxamide1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-aminohexan-1-oneN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-(1R)-cyclohexyl-2-oxoethyl)(phenylmethoxy)carboxamide(2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-amino-2-cyclohexylethan-1-oneN-((1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-(1S)-cyclohexyl-2-oxoethyl)(phenylmethoxy)carboxamide1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-amino-3,3-dimethylbutan-1-one1-{(3R)-3-((1R)-1-Hydroxyethyl)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(phenylmethoxy)ethan-1-one1-[(3R)-3-((1R)-1-Hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(phenylmethoxy)-ethan-1-one2-Benzyloxy-1-(3-((1R)-1-hydroxyethyl)-(3S,4S)-4-[4-methoxy-3-(1-methylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl)ethanone1-((3R)-3-((1R)-1-Hydroxyethyl)-4-{4-methoxy-3-[(methylcyclopropyl)methoxy]phenyl}-3-methylpyrrolidinyl)-2-hydroxyethan-1-one2Benzyloxy-1-[(3S,4S)-4-[3-(2-cyclopropylethoxy)-4-methoxyphenyl]-3-((1R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-{(3R)-3-((1R)-1-Hydroxyethyl)-4-[3-(2-cyclopropylethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one1-{(3R)-3-((1R)-1-Hydroxyethyl)-4-[3-(2-cyclopentylethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one1-[(3S,4S)-4-[3-(2-cyclopentylethoxy)-4-methoxyphenyl]-3-((1R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone2-Benzyloxy-1-[4-(S)-[3-(bicyclo[4.1.0]hept-7-yl-methoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-[4-(S)-[3-(Bicyclo[4.1.0]hept-7-ylmethoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone2-Benzyloxy-1-[4-(S)-[3-(bicyclo[3.1.0]hex-6-ylmethoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-[4-(S)-[3-(Bicyclo[3.1.0]hex-6-ylmethoxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone2-Benzyloxy-1-[4-(S)-[3-(4-tert-butylcyclohexyloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-[4-(S)-[3-(4-tert-Butylcyclohexyloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone2-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-methylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-methylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Benzyloxy-1-[4-(S)-[3-(decahydronaphthalen-2-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-[4-(S)-[3-(Decahydronaphthalen-2-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone2-Benzyloxy-1-[4-(S)-[3-(bicyclohexyl-4-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-[4-(S)-[3-(Bicyclohexyl-4-yloxy)-4-methoxyphenyl]-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone2-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-trifluoromethylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(4-trifluoromethylcyclohexyloxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(3-methoxy-3-methylbutoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(3-methoxy-3-methylbutoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phenylcyclopentylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phenylcyclopentylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Benzyloxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phenylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Hydroxy-1-{3-(S)-(1-(R)-hydroxyethyl)-4-(S)-[4-methoxy-3-(1-phenylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Benzyloxy-1-[(3S,4S)-4-3-(3-ethyloxetan-3-ylmethoxy)-4-methoxyphenyl]-3-((1R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-((3R)-3-((1R)-1-Hydroxyethyl)-4-{3-[(3-ethyloxetan-3-yl)methoxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-hydroxyethan-1-one(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoethylacetate2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoethylacetate2-Benzyloxy-1-[(3S,4S)-4-[3-(2-biphenyl-4-ylethoxy)-4-methoxyphenyl]-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]ethanone1-[(3S,4S)-4-[3-(2-Biphenyl-4-ylethoxy)-4-methoxyphenyl]-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-oxoethylacetate2-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-oxoethylacetate2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(dicyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoethylacetate2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one1-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-hydroxyethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(dicyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(3,3-dimethylbutoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(phenylmethoxy)ethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(3,3-dimethylbutoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(phenylmethoxy)ethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxyethan-1-oneN-(2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoethyl)(phenylmethoxy)carboxamide1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-aminoethan-1-one2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-1,1-dimethyl-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxy-2-methylpropan-1-one2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-methyl-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxypropan-1-one2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxo-1-phenylethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxy-2-phenylethan-1-one2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]3-methylpyrrolidinyl}-1-(4-fluorophenyl)-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-(4-fluorophenyl)-2-hydroxyethan-1-one({3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-carbonyl)cyclopropylacetate3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinylhydroxycyclopropyl ketone2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-(methylpropyl)-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxy-3-methylpentan-1-one2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-(2-methylpropyl)-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxy-4-methylpentan-1-one2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-2-oxo-1-benzylethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(2S)-2-hydroxy-3-phenylpropan-1-one(1R)-2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxo-1-benzylethylacetate((2R)-1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxy-3-phenylpropan-1-one2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}(1S)-1-methyl-2-oxoethylacetate2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-1-methyl-2-oxoethylacetate2-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}(1S)-1-methyl-2-oxoethylacetate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-(2S)-2-hydroxypropan-1-one2-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)-2-oxoethylacetate1-(3-((1R)-1-Hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinyl)(2S)-2-hydroxypropan-1-one2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(4-methoxy-3-{3-[4-(trifluoromethyl)phenyl]prop-2-ynyloxy}phenyl)-3-methylpyrrolidinyl](1S)-1-methyl-2-oxoethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(4-methoxy-3-{3-[4-(trifluoromethyl)phenyl]prop-2-ynyloxy}phenyl)-3-methylpyrrolidinyl](2S)-2-hydroxypropan-1-one2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-methoxyphenyl)-3-methylpyrrolidinyl](1S)-1-methyl-2-oxoethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}-4-methoxyphenyl)-3-methylpyrrolidinyl](2S)-2-hydroxypropan-1-one2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yl-oxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-(4-fluorophenyl)-2-oxoethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(4-fluorophenyl)-2-hydroxyethan-1-one2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1-methyl-2-oxoethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxypropan-1-one2-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-1,1-dimethyl-2-oxoethylacetate1-[3-((1R)-1-Hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxy-2-methylpropan-1-oneMethyl(3R)-3-((1R)-1-hydroxyethyl)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylate2-Hydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[2-(tetrahydrofuran-2-yl)ethoxy]phenyl}-3-methylpyrrolidin-1-yl)ethanone2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxy-ethyl)-4-[4-methoxy-3-(tetrahydrofuran-3-ylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanoneMethyl(3R)-3-((1R)-1-hydroxyethyl)-4-[3-((3S)-oxolan-3-yloxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylateMethyl(3R)-3-((1R)-1-hydroxyethyl)-4-[3-((3R)-oxolan-3-yloxy)-4-methoxyphenyl]-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-{3-[2-(4-fluorophenoxy)ethoxy]-4-methoxyphenyl}-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenoxy)propoxy]-4-methoxyphenyl}-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(4-methoxy-3-prop-2-ynyloxyphenyl)-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-but-2-ynyloxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinecarboxylateMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-{3-[3-(4-fluorophenyl)prop-2-ynyloxy]-4-methoxyphenyl}-3-methylpyrrolidinecarboxylate1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-acetylthioethan-1-one1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-sulfanylethan-1-one{2-[(3S,4S)-3-((R)-1-Hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidin-1-yl]-2-oxo-ethyl)carbamicacid tert-butyl ester2-Amino-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoromethylphenyl)-prop-2-ynyloxy]phenyl}-3-methylpyrrolidin-1-yl)ethanoneMethyl2-{3-((1R)-1-hydroxyethyl)(3S,4S)-4-[3-(tert-butoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-oxoacetateMethyl2-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoacetateMethyl2-{3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidinyl}-2-oxoacetate4-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(1,2-dihydroxyethyl)-3-methylpyrrolidine-1-carboxylicacid methyl ester[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-(2,2-dimethyl-[1,3]dioxolan-4-(S)-yl)methanone1-[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-(1-(R)-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-(S)-3-dihydroxypropan-1-one(R)-2,3-Dihydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[3-(indan-2-ylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidin-1-yl}propan-1-one(R)-1-[(3S,4S)-4-{3-[3-(4-Fluorophenoxy)propoxy]-4-methoxyphenyl}-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2,3-dihydroxypropan-1-one1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoromethylphenyl)prop-2-ynyloxy]phenyl}-3-methylpyrrolidin-1-yl)methanone(R)-2,3-Dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[3-(4-trifluoromethylphenyl)-prop-2-ynyloxy]phenyl}-3-methylpyrrolidin-1-yl)-propan-1-one2-Benzyloxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(2-thiophen-3-yl-ethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-((R)-2-phenylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone1-[(3S,4S)-4-[3-(3-Cyclopentylpropoxy)-4-methoxyphenyl]-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl]-2-hydroxyethanone2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylpropoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[3-(1-hydroxyindan-2-yloxy)-4-methoxyphenyl]-3-methylpyrrolidin-1-yl}ethanone2-Hydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-{4-methoxy-3-[2-(4-methoxyphenyl)ethoxy]phenyl}-3-methylpyrrolidin-1-yl)ethanone2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-((R)-2-methylcyclopropylmethoxy)phenyl]-3-methylpyrrolidin-1-yl}ethanone1-(R)-[1-(2-Benzyloxyethyl)-4-(S)-(3-cyclopentyloxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]-ethanol1-(R)-[4-(S)-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-hydroxyethyl)-3-(S)-methylpyrrolidin-3-yl]ethanol2-Benzyloxy-1-[4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-hydroxymethyl-3-methylpyrrolidin-1-yl]ethanone1-(2-Benzyloxyacetyl)-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidine-3-carbaldehyde1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-[(3S,4S)-3-((R)-1-hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidin-1-yl]methanone1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin[1[yl}methanone(R)-2,3-Dihydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}propan-1-one1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-[(3S,4S)-3-((R)-1-hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidin-1-yl]methanone1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-{(3S,4S)-3-((R)1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}methanone(S)-2,3-Dihydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}propan-1-oneAcetic acid(S)-1-benzyl-2-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}-2-oxoethylester(S)-2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}-3-phenylpropan-1-oneMethyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylateand{2-[(3S,4S)-3-((R)-1-Hydroxyethyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methylpyrrolidin-1-yl]-2-oxo-ethyl)carbamicacid tert-butyl ester.
 12. The compound of claim 1 selected from thegroup consisting of:1-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-(phenylmethoxy)ethan-1-one,phenylmethyl4-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-4-oxobutanoate,N-{3-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-3-oxopropyl}(phenylmethoxy)carboxamide,N-{2-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-oxoethyl}(phenylmethoxy)carboxamide,1-[3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidinyl]-2-hydroxyethan-1-one,(1R)-1-[(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-(3-pyridyl)pyrrolidin-3-yl]ethan-1-ol,(1R)-1-[(3S,4S)-4-(3-indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-pyrimidin-2-ylpyrrolidin-3-yl]ethan-1-ol,methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylate,methyl3-((1R)-1-hydroxyethyl)(3R,4R)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinecarboxylate,methyl3-((1R)-1-hydroxyethyl)(3S,4S)-4-[4-methoxy-3-(3-phenylpropoxy)phenyl]-3-methylpyrrolidinecarboxylate,3-((1R)-1-hydroxyethyl)(3S,4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidinylmorpholin-4-yl ketone,1-{(3S,4S)-3-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxypentan-1-one,1-{(3S,4S)-((1R)-1-Hydroxyethyl)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl)}(2R)-2-amino-3-hydroxypropan-1-onehydrochloride,1-{3-((1R)-1-Hydroxyethyl)(3S,4S)-4-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidinyl}-2-hydroxy-2-phenylethan-1-one,(S)-2,3-Dihydroxy1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}propan-1-one,and(S)-2-Hydroxy-1-{(3S,4S)-3-((R)-1-hydroxyethyl)-4-[4-methoxy-3-(3-phenylprop-2-ynyloxy)phenyl]-3-methylpyrrolidin-1-yl}-3-phenylpropan-1-one.13. The compound of claim 1 selected from the group consisting of:


14. A compound of claim 1 selected from the group consisting of:


15. The compound of claim 1 having an IC₅₀ vs. human recombinant PDE4 ofabout 700 pM to about 15 μM.
 16. The compound of claim 1 having aPBL/TNFα EC₅₀ of about 1 nM to about 20 μM.
 17. The compound of claim 1having an IC₅₀ vs. human recombinant PDE4 of about 700 pM to about 15μM, and a PBL/TNFα EC₅₀ of about 1 nM to about 20 μM.
 18. The compoundof claim 1 having an IC₅₀ vs. human recombinant PDE4 of about 100×10⁻⁹ Mor less.
 19. The compound of claim 1 having an IC₅₀ vs. humanrecombinant PDE4 of about 50×10⁻⁹ M or less.
 20. The compound of claim 1having a PBL/TNFα EC₅₀ of about 500×10⁻⁹ M or less.
 21. The compound ofclaim 1 having a PBL/TNFα EC₅₀ of about 100×10⁻⁹ M or less.
 22. Thecompound of claim 1 having an IC₅₀ vs. human recombinant PDE4 of about100×10⁻⁹ or less and a PBL/TNFα EC₅₀ of about 500×10⁻⁹ M or less. 23.The compound of claim 1 having an IC₅₀ vs. human recombinant PDE4 ofabout 50×10⁻⁹ or less and a PBL/TNFα EC₅₀ of about 100×10⁻⁹ M or less.24. A pharmaceutical composition comprising a compound of claim 1, apharmaceutically acceptable carrier, and, optionally, a secondantiinflammatory therapeutic agent.
 25. The composition of claim 24wherein the second antiinflammatory therapeutic agent is capable oftargeting TNFα.
 26. A method of treating a mammal having a conditionwhere inhibition of a cAMP-specific PDE is of therapeutic benefit, saidmethod comprising administering to said mammal at therapeuticallyeffective amount of a compound of claim
 1. 27. A method of modulatingcAMP levels in a mammal comprising administering to said mammal aneffective amount of a compound of claim
 1. 28. A method of treating amammal having a condition where inhibition of a cAMP-specific PDE is ofa therapeutic benefit comprising administering to said mammal aneffective amount of a pharmaceutical composition comprising a compoundof claim 1 and a pharmaceutically acceptable carrier.
 29. The method ofclaim 28 wherein the condition is an allergic disease, an autoimmunedisease, an inflammatory disease, an arthritic disease, or dermititis.30. The method of claim 28 wherein the condition is rheumatoidarthritis, osteoarthritis, gouty arthritis, or spondylitis.
 31. Themethod of claim 28 wherein the condition is thyroid-associatedophthalmopathy, Behcet disease, sepsis, septic shock, endotoxic shock,gram negative sepsis, gram positive sepsis, toxic shock syndrome,allergic conjunctivitis, vernal conjunctivitis, or eosinophilicgranuloma.
 32. The method of claim 28 wherein the condition is asthma,chronic bronchitis, allergic rhinitis, adult respiratory distresssyndrome, chronic pulmonary inflammatory disease, chronic obstructivepulmonary disease, silicosis, or pulmonary sarcoidosis.
 33. The methodof claim 28 wherein the condition is reperfusion injury of themyocardium, brain or extremities as a brain or spinal cord injury due totrauma.
 34. The method of claim 28 wherein the condition is a fibrosis,keloid formation, or scar tissue formation.
 35. The method of claim 28wherein the condition is systemic lupus erythematosus, a transplantrejection disorder, a graft vs. host reaction, or an allograftrejection.
 36. The method of claim 28 wherein the condition is chronicglomerulonephritis, nephropathy attributed to Type 2 diabetes, aninflammatory bowel disease, Crohn's disease, or ulcerative colitis. 37.The method of claim 28 wherein the condition is proliferativelymphocytic disease or a leukemia.
 38. The method of claim 28 whereinthe condition is an inflammatory dermatosis, atopic dermatitis,psoriasis, or urticaria.
 39. The method of claim 28 wherein thecondition is a cardiomyopathy, congestive heart failure,atherosclerosis, pyrexia, cachexia, cachexia secondary to infection ormalignancy, cachexia secondary to acquired immune deficiency syndrome,ARC, cerebral malaria, osteoporosis, a bone resorption disease, feverand myalgias due to infection, erectile dysfunction, male or femaleinfertility, diabetes insipidus, a central nervous system disorder, ananxiety or stress response, cerebral ischemia, tardive dyskinesia,Parkinson's Disease, or premenstrual syndrome.
 40. The method of claim28 wherein the condition is depression or multi-infarct dementia. 41.The method of claim 40 further comprising treatment with a secondantidepression therapy.
 42. The method of claim 41 wherein the secondantidepression therapy is selected from the group consisting of anelectroconvulsive procedure, a monoamine oxidase inhibitor, a selectionreuptake inhibitor of serotonin, and a selection reuptake inhibitor ofnorepinephrine.
 43. The method of claim 28 wherein the condition isobesity.
 44. The method of claim 43 further comprising administration ofa PDE3 inhibitor.
 45. The method of claim 28 wherein the mammal exhibitsminimal adverse central nervous system side effects.
 46. The method ofclaim 28 wherein the mammal is free of adverse central nervous systemside effects.
 47. The method of claim 28 wherein the mammal exhibits aminimal emetic response.
 48. The method of claim 28 wherein the mammalis free of an emetic response.
 49. A method of reducing TNF levels in amammal comprising administering to said mammal therapeutically effectiveamount of a compound of claim
 1. 50. A method of suppressinginflammatory cell activation in a mammal comprising administering tosaid mammal a therapeutically effective amount of a compound of claim 1.51. A method of inhibiting PDE4 function in a mammal comprisingadministering to said mammal a therapeutically effective amount of acompound of claim
 1. 52. A compound having a formula:

wherein R¹ is selected from the group consisting of hydrogen, loweralkyl, bridged alkyl, aryl, cycloalkyl, a 4-, 5-, or 6-memberedsaturated heterocycle, heteroaryl, C₁₋₄alkylenearyl, C₁₋₄alkyleneOaryl,C₁₋₄alkyleneheteroaryl, C₁₋₄alkyleneHet, C₂₋₄alkylenearylOaryl,C₁₋₄alkylene bridged alkyl, C₁₋₄alkylenecycloalkyl, substituted orunsubstituted propargyl, substituted or unsubstituted allyl, andhalocycloalkyl; R² is selected from the group consisting of hydrogen,methyl, and halo-substituted methyl; R³ is selected from the groupconsisting of hydrogen, C₁₋₄alkylenearyl, andC(═O)C₁₋₃alkyleneOC₁₋₃-alkylenearyl; R⁴ is selected from the groupconsisting of hydrogen, lower alkyl, haloalkyl, cycloalkyl, and aryl; R⁵is selected from the group consisting of hydrogen, lower alkyl, alkynyl,haloalkyl, hydroxyalkyl, cycloalkyl, and aryl; R⁶ is selected from thegroup consisting of hydrogen, lower alkyl, and C(═O)R⁷; R⁷is selectedfrom the group consisting of lower alkyl, branched or unbranched,C₁₋₄alkylenearyl, cycloalkyl, Het, C₁₋₄alkylenecycloalkyl, heteroaryl,and aryl, each optionally substituted with one or more of OC(═O)R⁸,C(═O)OR⁸, OR⁸, NR⁸R⁹, and SR⁸; and R⁸ and R⁹, same or different, areselected from the group consisting of hydrogen, lower alkyl, cycloalkyl,aryl, heteroaryl, C(═O)Oalkyl, C(═O)-alkyl, C(O)Oaryl, alkylSO₂,haloalkylSo₂, C(═O)C₁₋₃alkylenearyl, C(═O)OC₁₋₄alkylenearyl,C₁₋₄alkylenearyl, and Het, or R⁸ and R⁹ together form a 4-membered to7-membered ring; R¹⁰ is selected from the group consisting of hydrogen,alkyl, haloalkyl, cycloalkyl, aryl, C(═O)alkyl, C(═O)cycloalkyl,C(═O)aryl, C(═O)Oalkyl, C(═O)Ocycloalkyl, C(═O)aryl, CH₂OH, CH₂Oalkyl,CHO, CN, NO₂, and SO₂R¹¹; and R¹¹ is selected from the group consistingof alkyl, cycloalkyl, trifluoromethyl, aryl, aralkyl, and NR⁸R⁹; andsalts and solvates thereof.
 53. The compound of claim 52 selected fromthe group consisting of:(±)-[1-Benzyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]methanol2-[l-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]propan-2-ol2-[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]propan-2-ol2-Benzyloxy-1-[4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(l-hydroxy-1-methylethyl)-3-(S)-methylpyrrolidin-1-yl]ethanone(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidin-3-yl]ethan-1-ol(1R)-1-[(3S,4S)-4-(3-Indan-2-yloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethan-1-ol(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidin-3-yl]ethan-1-ol(1S)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-benzylpyrrolidin-3-yl]ethan-1-ol(1S)-1-{(3S,4S)-4-[4-Methoxy-3-(phenylmethoxy)phenyl]-3-methyl-1-benzylpyrrolidin-3-yl}ethan-1-ol(1R)-1-((3S,4S)-4-[4-Methoxy-3-(phenylmethoxy)phenyl]-3-methyl-1-benzylpyrrolidin-3-yl}ethan-1-ol1-R-[1-Benzyl-4-S-(3-tert-butoxy-4-methoxyphenyl)-3-S-methylpyrrolidin-3-yl]ethanol3-[1-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidine-3-carbonyl]-4-(R)-phenyloxazolidin-2-one1-[1-Benzyl-4-(S)-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]ethanol(1R)-1-{(3S,4S)-4-[3-(Cyclopropylmethoxy)-4-methoxyphenyl]-3-methylpyrrolidin-3-yl}ethan-1-ol(1R)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethan-1-ol(1S)-1-[(3S,4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methylpyrrolidin-3-yl]ethan-1-ol5-[4-((1R)-1-Hydroxyethyl)(3S,4S)-4-methylpyrrolidin-3-yl]-2-methoxyphenol(1R)-1-{(3R)-4-[3-(tert-Butoxy)-4-methoxyphenyl]-3-methyl-1-benzylpyrrolidin-3-yl}ethan-1-ol5-[(4R)-4-((1S)-1-Hydroxyethyl)-4-methyl-1-benzylpyrrolidin-3-yl]-2-methoxyphenol[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]methanol.